Journal articles: 'Virtual agent synthesis'

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Randhavane, Tanmay, Aniket Bera, and Dinesh Manocha. "F2FCrowds: Planning Agent Movements to Enable Face-to-Face Interactions." Presence: Teleoperators and Virtual Environments 26, no. 2 (May 1, 2017): 228–46. http://dx.doi.org/10.1162/pres_a_00294.

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The simulation of human behaviors in virtual environments has many applications. In many of these applications, situations arise in which the user has a face-to-face interaction with a virtual agent. In this work, we present an approach for multi-agent navigation that facilitates a face-to-face interaction between a real user and a virtual agent that is part of a virtual crowd. In order to predict whether the real user is approaching a virtual agent to have a face-to-face interaction or not, we describe a model of approach behavior for virtual agents. We present a novel interaction velocity prediction (IVP) algorithm that is combined with human body motion synthesis constraints and facial actions to improve the behavioral realism of virtual agents. We combine these techniques with full-body virtual crowd simulation and evaluate their benefits by conducting a user study using Oculus HMD in an immersive environment. Results of this user study indicate that the virtual agents using our interaction algorithms appear more responsive and are able to elicit more reaction from the users. Our techniques thus enable face-to-face interactions between a real user and a virtual agent and improve the sense of presence observed by the user.

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Putnam, Lance, William Latham, and Stephen Todd. "Flow Fields and Agents for Immersive Interaction in Mutator VR: Vortex." Presence: Teleoperators and Virtual Environments 26, no. 2 (May 1, 2017): 138–56. http://dx.doi.org/10.1162/pres_a_00290.

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This article discusses the challenges in creating Mutator VR: Vortex, a virtual reality experience based on interaction with semi-autonomous, organically inspired agents. The work allows the immersant to morph between a vast number of procedurallygenerated microworlds, each with its own visual elements, sounds, agent dynamics, and user interactions. We outline two methods used for procedural generation that are based fundamentally on integration of different modalities. Curve-based synthesis is used for simultaneous generation of entity sounds and shape and flow grains are employed to determine both agent dynamics and user interaction with the agents.

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Lee, Hojin, and Cheolhyeon Kwon. "Distributed Control-Estimation Synthesis for Stochastic Multi-Agent Systems via Virtual Interaction Between Non-Neighboring Agents." IEEE Control Systems Letters 6 (2022): 848–53. http://dx.doi.org/10.1109/lcsys.2021.3086848.

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Mavropoulos, Thanassis, Georgios Meditskos, Spyridon Symeonidis, Eleni Kamateri, Maria Rousi, Dimitris Tzimikas, Lefteris Papageorgiou, et al. "A Context-Aware Conversational Agent in the Rehabilitation Domain." Future Internet 11, no. 11 (November 1, 2019): 231. http://dx.doi.org/10.3390/fi11110231.

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Conversational agents are reshaping our communication environment and have the potential to inform and persuade in new and effective ways. In this paper, we present the underlying technologies and the theoretical background behind a health-care platform dedicated to supporting medical stuff and individuals with movement disabilities and to providing advanced monitoring functionalities in hospital and home surroundings. The framework implements an intelligent combination of two research areas: (1) sensor- and camera-based monitoring to collect, analyse, and interpret people behaviour and (2) natural machine–human interaction through an apprehensive virtual assistant benefiting ailing patients. In addition, the framework serves as an important assistant to caregivers and clinical experts to obtain information about the patients in an intuitive manner. The proposed approach capitalises on latest breakthroughs in computer vision, sensor management, speech recognition, natural language processing, knowledge representation, dialogue management, semantic reasoning, and speech synthesis, combining medical expertise and patient history.

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Arshad, Uzma, Sibtain Ahmed, Nusrat Shafiq, Zaheer Ahmad, Aqsa Hassan, Naseem Akhtar, Shagufta Parveen, and Tahir Mehmood. "Structure-Based Designing, Solvent Less Synthesis of 1,2,3,4-Tetrahydropyrimidine-5-carboxylate Derivatives: A Combined In Vitro and In Silico Screening Approach." Molecules 26, no. 15 (July 22, 2021): 4424. http://dx.doi.org/10.3390/molecules26154424.

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Objective: In this study, small molecules possessing tetrahydropyrimidine derivatives have been synthesized having halogenated benzyl derivatives and carboxylate linkage. As previously reported, FDA approved halogenated pyrimidine derivatives prompted us to synthesize novel compounds in order to evaluate their biological potential. Methodology: Eight pyrimidine derivatives have been synthesized from ethyl acetoacetate, secondary amine, aromatic benzaldehyde by adding catalytic amount of CuCl2·2H2O via solvent less Grindstone multicomponent reagent method. Molecular structure reactivity and virtual screening were performed to check their biological efficacy as an anti-oxidant, anti-cancer and anti-diabetic agent. These studies were supported by in vitro analysis and QSAR studies. Results: After combined experimental and virtual screening 5c, 5g and 5e could serve as lead compounds, having low IC50 and high binding affinity.

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Andrianov, A. M., Yu V. Kornoushenko, A. D. Karpenko, and A. V. Tuzikov. "Identification of potential inhibitors of coronavirus SARS-CoV-2 using the methods of virtual screening and molecular modeling." Doklady of the National Academy of Sciences of Belarus 64, no. 3 (July 9, 2020): 308–16. http://dx.doi.org/10.29235/1561-8323-2020-64-3-308-316.

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To find small-molecule compounds that can simulate the structural and functional properties of the high affinity X77 ligand of the main protease of SARS-CoV-2 - etiologic agent of COVID-19, the virtual screening of 9 molecular libraries of the Pharmit web server containing over 213.5 million chemical structures was performed. Using molecular modeling, the neutralizing activity of the identified molecules was evaluated, resulting in 5 leader compounds promising for synthesis and testing for antiviral activity. The data obtained indicate that these compounds may be used as basic structures for the development of effective drugs to treat the novel coronavirus infection.

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MARTIN, JEAN-CLAUDE, RADOSLAW NIEWIADOMSKI, LAURENCE DEVILLERS, STEPHANIE BUISINE, and CATHERINE PELACHAUD. "MULTIMODAL COMPLEX EMOTIONS: GESTURE EXPRESSIVITY AND BLENDED FACIAL EXPRESSIONS." International Journal of Humanoid Robotics 03, no. 03 (September 2006): 269–91. http://dx.doi.org/10.1142/s0219843606000825.

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One of the challenges of designing virtual humans is the definition of appropriate models of the relation between realistic emotions and the coordination of behaviors in several modalities. In this paper, we present the annotation, representation and modeling of multimodal visual behaviors occurring during complex emotions. We illustrate our work using a corpus of TV interviews. This corpus has been annotated at several levels of information: communicative acts, emotion labels, and multimodal signs. We have defined a copy-synthesis approach to drive an Embodied Conversational Agent from these different levels of information. The second part of our paper focuses on a model of complex (superposition and masking of) emotions in facial expressions of the agent. We explain how the complementary aspects of our work on corpus and computational model is used to specify complex emotional behaviors.

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Masloboev, A. V. "Software system «Network-centric managerial structures synthesizer»." Informacionno-technologicheskij vestnik 14, no. 4 (December 30, 2017): 145–55. http://dx.doi.org/10.21499/2409-1650-2017-4-145-155.

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For practical applications and problem-solving of regional security management information support on the basis of combined simulation-expert modeling a special-purpose software system «Network-centric managerial structures synthesizer» has been developed. Software system provides agent-based model automated synthesis and analysis of the networked virtual managerial structures for security support under crisis situations in socio-economic sphere of regional development. System simulation and software toolkit allows alternative modeling scenario spectrum formation, analysis and extension of regional crisis situations. That provides managerial decision-making information probability and validity in the field of regional security support.

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Chen, Kuan-Chung, Hsin-Yi Chen, and Calvin Yu-Chian Chen. "Potential Protein Phosphatase 2A Agents from Traditional Chinese Medicine against Cancer." Evidence-Based Complementary and Alternative Medicine 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/436863.

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Protein phosphatase 2A (PP2A) is an important phosphatase which regulates various cellular processes, such as protein synthesis, cell growth, cellular signaling, apoptosis, metabolism, and stress responses. It is a holoenzyme composed of the structural A and catalytic C subunits and a regulatory B subunit. As an environmental toxin, okadaic acid, is a tumor promoter and binds to PP2A catalytic C subunit and the cancer-associated mutations in PP2A structural A subunit in human tumor tissue; PP2A may have tumor-suppressing function. It is a potential drug target in the treatment of cancer. In this study, we screen the TCM compounds in TCM Database@Taiwan to investigate the potent lead compounds as PP2A agent. The results of docking simulation are optimized under dynamic conditions by MD simulations after virtual screening to validate the stability of H-bonds between PP2A-αprotein and each ligand. The top TCM candidates, trichosanatine and squamosamide, have potential binding affinities and interactions with key residues Arg89 and Arg214 in the docking simulation. In addition, these interactions were stable under dynamic conditions. Hence, we propose the TCM compounds, trichosanatine and squamosamide, as potential candidates as lead compounds for further study in drug development process with the PP2A-αprotein.

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Malki, Ahmed, Doaa A. E. Issa, Rasha Y. Elbayaa, and Hayam M. A. Ashour. "Design and Synthesis of Novel Thioethers Derived from 1,5-Diphenyl-6- thioxo-6,7-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones as Antiangiogenic Agents." Letters in Drug Design & Discovery 16, no. 2 (November 29, 2018): 200–212. http://dx.doi.org/10.2174/1570180815666180518112321.

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Background: In attempts to discover new antiangiogenic entities, a novel series of thioethers derived from 6-thioxo-6,7-dihydro-1H-pyrazolo[3,4-d]pyrimidine-4(5H)ones was considered and designed. </P><P> Methods: Virtual screening was carried out through docking of the compounds into the vascular endothelial growth factor and matrix metalloproteinase-9 binding sites. Molecular docking studies were performed using Lamarckian Genetic Algorithm. Compounds possessing lowest ligandprotein pairwise interaction energies were synthesized and screened for their antiproliferative activities against five cancer cell lines namely MHCC97H (liver), MDA-MB 231 (Breast), Colo205 (Colon), A549 (lung), A498 (kidney) and IC50 values were determined for the most potent compounds. Additionally, they were tested for their antiangiogenic activities by testing their ability to inhibit Human Umbilical Vein Endothelial Cell (HUVEC), cord formation and migration in response to chemoattractant. Results: Three compounds 2a, 2b and 5b showed significant antiangiogenic activities. The allyl thioether 2b was the most active with chemotaxis activity data nearly comparable to that of the positive control, TNP-470. Additionally, 2a, 2b and 5b, contrary to TNP-470, interfered with the migration of HUVECs in response to vascular endothelial growth factor rather than endothelial cells proliferation or cord formation. Compounds 2a, 2b and 5b were also investigated for their inhibitory effects on MMPs to investigate the relationship between their angiogenic activity and MMPs. Results revealed that compound 2b was the most effective MMP-9 inhibitor in this series. Additionally, compound 2b reduced the expression levels of VEGF and pERK1/2. Conclusion: Our results suggest that compound 2b is considered as a promising antiangiogenic agent by targeting VEGF and MMP-9.

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Patel, Harun M., Pankaj Bari, Rajshekhar Karpoormath, Malleshappa Noolvi, Neeta Thapliyal, Sanjay Surana, and Pritam Jain. "Design and synthesis of VEGFR-2 tyrosine kinase inhibitors as potential anticancer agents by virtual based screening." RSC Advances 5, no. 70 (2015): 56724–71. http://dx.doi.org/10.1039/c5ra05277g.

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Margetis, George, Konstantinos C. Apostolakis, Stavroula Ntoa, George Papagiannakis, and Constantine Stephanidis. "X-Reality Museums: Unifying the Virtual and Real World Towards Realistic Virtual Museums." Applied Sciences 11, no. 1 (December 31, 2020): 338. http://dx.doi.org/10.3390/app11010338.

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Culture is a field that is currently entering a revolutionary phase, no longer being a privilege for the few, but expanding to new audiences who are urged to not only passively consume cultural heritage content, but actually participate and assimilate it on their own. In this context, museums have already embraced new technologies as part of their exhibitions, many of them featuring augmented or virtual reality artifacts. The presented work proposes the synthesis of augmented, virtual and mixed reality technologies to provide unified X-Reality experiences in realistic virtual museums, engaging visitors in an interactive and seamless fusion of physical and virtual worlds that will feature virtual agents exhibiting naturalistic behavior. Visitors will be able to interact with the virtual agents, as they would with real world counterparts. The envisioned approach is expected to not only provide refined experiences for museum visitors, but also achieve high quality entertainment combined with more effective knowledge acquisition.

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Rampioni, Margherita, Vera Stara, Elisa Felici, Lorena Rossi, and Susy Paolini. "Embodied Conversational Agents for Patients With Dementia: Thematic Literature Analysis." JMIR mHealth and uHealth 9, no. 7 (July 16, 2021): e25381. http://dx.doi.org/10.2196/25381.

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Background As the world’s population rapidly ages, the number of older adults with cognitive impairment will also increase. Several studies have identified numerous complex needs of people with dementia, which assistive technologies still fail to support. Recent trends have led to an increasing focus on the use of embodied conversational agents (ECAs) as virtual entities able to interact with a person through natural and familiar verbal and nonverbal communication. The use of ECAs could improve the accessibility and acceptance of assistive technologies matching those high-level needs that are not well covered to date. Objective The aim of this thematic literature analysis was to map current studies in the field of designing ECAs for patients with dementia in order to identify the existing research trend and possible gaps that need to be covered in the near future. The review questions in this study were as follows: (1) what research frameworks are used to study the interaction between patients with dementia and ECAs? (2) what are the findings? and (3) what are the barriers reported in these studies? Methods Separate literature searches were conducted in PubMed, Web of Science, Scopus, and Embase databases by using specific umbrella phrases to target the population (patients with dementia) and the technology-based intervention (embodied conversational agent). Studies that met the inclusion criteria were appraised through the Mixed Methods Appraisal Tool and then discussed in a thematic analysis. Results The search process identified 115 records from the databases and study references. After duplicates (n=45) were removed, 70 papers remained for the initial screening. A total of 7 studies were finally included in the qualitative synthesis. A thematic analysis of the reviewed studies identified major themes and subthemes: the research frameworks used to gather users’ perspectives on ECAs (theme 1), the insights shared by the 7 studies as well as the value of user involvement in the development phases and the challenge of matching the system functionalities with the users’ needs (theme 2), and the main methodological and technical problems faced by each study team (theme 3). Conclusions Our thematic literature analysis shows that the field of ECAs is novel and poorly discussed in the scientific community and that more sophisticated study designs and proofs of efficacy of the approach are required. Therefore, by analyzing the main topic of the narrative review, this study underscores the challenge of synchronizing and harmonizing knowledge, efforts, and challenges in the dementia care field and its person-centered paradigm through the user-centered design approach. Enabling strict collaboration between interdisciplinary research networks, medical scientists, technology developers, patients, and their formal and informal caregivers is still a great challenge in the field of technologies for older adults.

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Polishchuk, Pavel G., Georgiy V. Samoylenko, Tetiana M. Khristova, Olga L. Krysko, Tatyana A. Kabanova, Vladimir M. Kabanov, Alexander Yu Kornylov, et al. "Design, Virtual Screening, and Synthesis of Antagonists of αIIbβ3as Antiplatelet Agents." Journal of Medicinal Chemistry 58, no. 19 (September 25, 2015): 7681–94. http://dx.doi.org/10.1021/acs.jmedchem.5b00865.

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Klimenko, Kyrylo, Sergey Lyakhov, Marina Shibinskaya, Alexander Karpenko, Gilles Marcou, Dragos Horvath, Marina Zenkova, et al. "Virtual screening, synthesis and biological evaluation of DNA intercalating antiviral agents." Bioorganic & Medicinal Chemistry Letters 27, no. 16 (August 2017): 3915–19. http://dx.doi.org/10.1016/j.bmcl.2017.06.035.

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Alonso, Carolina Maria do Carmo, Pascal Daniel Béguin, and Francisco José de Castro Moura Duarte. "Work of community health agents in the Family Health Strategy: meta-synthesis." Revista de Saúde Pública 52 (February 26, 2018): 14. http://dx.doi.org/10.11606/s1518-8787.2018052000395.

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OBJECTIVE: To systematize and analyze the evidence from qualitative studies that address the perception of Brazilian Community Health Agents about their work. METHODS: This is a systematic review of the meta-synthesis type on the work of community health agents, carried out from the Virtual Health Library using the descriptors “Agente Comunitário de Saúde” and “Trabalho”, in Portuguese. The strategy was constructed by crossing descriptors, using the Boolean operator “AND”, and filtering Brazilian articles, published from 2004 to 2014, which resulted in 129 identified articles. We removed quantitative or quanti-qualitative research articles, essays, debates, literature reviews, reports of experiences, and research that did not include Brazilian Community Health Agents as subjects. Using these criteria, we selected and analyzed 33 studies that allowed us to identify common subjects and differences between them, to group the main conclusions, to classify subjects, and to interpret the content. RESULTS: The analysis resulted in three thematic units: characteristics of the work of community health agents, problems related to the work of community health agents, and positive aspects of the work of community health agents. On the characteristics, we could see that the work of the community health agents is permeated by the political and social dimensions of the health work with predominant use of light technologies. The main input is the knowledge that this professional obtains with the contact with families, which is developed with home visits. On the problems in the work of community health agents, we could identify the lack of limits in their attributions, poor conditions, obstacles in the relationship with the community and teams, weak professional training, and bureaucracy. The positive aspects we identified were the recognition of the work by families, resolution, bonding, work with peers, and work close to home. CONCLUSIONS: This review provided an overview of the difficulties and positive aspects that are present in the daily work of community health agents. Given this, we have raised two challenges. The first one refers to how public policy makers need to appropriation the research results and the second one refers to the need to invest in studies that are designed to generate solutions for the difficulties faced by community health agents in their work.

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Oyedele, Abiodun S., Deanna N. Bogan, and Cosmas O. Okoro. "Synthesis, biological evaluation and virtual screening of some acridone derivatives as potential anticancer agents." Bioorganic & Medicinal Chemistry 28, no. 9 (May 2020): 115426. http://dx.doi.org/10.1016/j.bmc.2020.115426.

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Repetsky, S. P., I. G. Vyshyvana, H. M. Kuznietsova, V. K. Rybalchenko, S. P. Kruchinin, O. I. Tykhoniuk, D. S. Milokhov, O. V. Khilyax, and R. M. Melnyk. "Models nanocomplexes based on C60 fullerene for creation of biologically active agents for medicine." Modern Physics Letters B 34, no. 19n20 (July 9, 2020): 2040064. http://dx.doi.org/10.1142/s0217984920400643.

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Complex drugs based on C[Formula: see text] fullerence and pyrrole derivatives are promising for the development of antitumor and anti-inflammatory agents for use in targeted therapy, but have little efficiency in the synthesis of such complexes and have virtually no stable synthesis products with fullerene. The stability of the nanocomplex based on [60] PCBA and the intermediate compound based on “[Formula: see text]-pyrrole-2,5-dione” effective for the synthesis of targeted therapeutic agents was investigated by means of numerical calculations. The application of quantum-chemical methods in the Gaussian package establishes the stability of the nanocomplex at human body temperatures, the possibility of using such complexes for further study of the therapeutic properties of the individual components of the decomposition products of the nanocomplex.

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Barker, David, Lisa Ivy Pilkington, Natalie Haverkate, Euphemia Leung, and Johannes Reynisson. "Development of Thienopyridines as Potent Antiproliferative Agents." Proceedings 22, no. 1 (August 6, 2019): 2. http://dx.doi.org/10.3390/proceedings2019022002.

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Virtual high throughput screening of a large compound library against the regulatory enzyme phospholipase C (PLC) led to the discovery of the thieno[2,3-b]pyridine-2-carboxamides as potential inhibitors. Subsequent biological testing verified the antiproliferative activity of this compound class. Morphology and motility assays, using a number of triple negative breast cancer cell lines, led to the conclusion that PLC is the most probable biomolecular target. Using a combination of computer-aided drug design and synthesis, further analogues have been prepared and tested for their antiproliferative activity, allowing a comprehensive SAR to be developed. Numerous analogues with low nano-molar growth inhibition against various cancers have been prepared. SAR studies suggest that the core structure can be fine-tuned to specific cancers, potentially due to enzyme/isoform specificity. Additionally, mouse xenograft assays showed significant reduction in tumour size after treatment, whilst showing no adverse effects to non-cancerous mice. Here, we report on our recent development of novel thienopyridines and derivatives, expanding the SAR against PLC, and our efforts to prepare potent, soluble, and bioavailable compounds.

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El Bakkali, Mustapha, Lhassane Ismaili, Isabelle Tomassoli, Laurence Nicod, Marc Pudlo, and Bernard Refouvelet. "Pharmacophore Modelling and Synthesis of Quinoline-3-Carbohydrazide as Antioxidants." International Journal of Medicinal Chemistry 2011 (March 28, 2011): 1–10. http://dx.doi.org/10.1155/2011/592879.

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From well-known antioxidants agents, we developed a first pharmacophore model containing four common chemical features: one aromatic ring and three hydrogen bond acceptors. This model served as a template in virtual screening of Maybridge and NCI databases that resulted in selection of sixteen compounds. The selected compounds showed a good antioxidant activity measured by three chemical tests: DPPH radical, OH∘ radical, and superoxide radical scavenging. New synthetic compounds with a good correlation with the model were prepared, and some of them presented a good antioxidant activity.

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Huo, Jingqian, Bin Zhao, Zhe Zhang, Jihong Xing, Jinlin Zhang, Jingao Dong, and Zhijin Fan. "Structure-Based Discovery and Synthesis of Potential Transketolase Inhibitors." Molecules 23, no. 9 (August 23, 2018): 2116. http://dx.doi.org/10.3390/molecules23092116.

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Transketolase (TKL) plays a key role in plant photosynthesis and has been predicted to be a potent herbicide target. Homology modeling and molecular dynamics simulation were used to construct a target protein model. A target-based virtual screening was developed to discover novel potential transketolase inhibitors. Based on the receptor transketolase 1 and a target-based virtual screening combined with structural similarity, six new compounds were selected from the ZINC database. Among the structural leads, a new compound ZINC12007063 was identified as a novel inhibitor of weeds. Two novel series of carboxylic amide derivatives were synthesized, and their structures were rationally identified by NMR and HRMS. Biological evaluation of the herbicidal and antifungal activities indicated that the compounds 4u and 8h were the most potent herbicidal agents, and they also showed potent fungicidal activity with a relatively broad-spectrum. ZINC12007063 was identified as a lead compound of potential transketolase inhibitors, 4u and 8h which has the herbicidal and antifungal activities were synthesized based on ZINC12007063. This study lays a foundation for the discovery of new pesticides.

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Azad, Iqbal, Rumana Ahmad, Tahmeena Khan, Mohammad Saquib, Firoj Hassan, Yusuf Akhter, Abdul R. Khan, and Malik Nasibullah. "Phenanthridine derivatives as promising new anticancer agents: synthesis, biological evaluation and binding studies." Future Medicinal Chemistry 12, no. 8 (April 2020): 709–39. http://dx.doi.org/10.4155/fmc-2019-0016.

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Aim: Phenanthridines are an essential class of nitrogenous heterocycles with extensive applications in medicinal chemistry. The development of efficient and eco-friendly methods for the preparation of chirally pure dihydropyrrolo[1,2- f]phenanthridines (5a–h), and their in vitro evaluation and modeling studies as potential anticancer, antioxidant and DNA cleavage agents is reported. Methodology & results: Compounds 5a–h were prepared through a facile one-pot synthesis and characterized by infrared, high resolution mass spectrometry, 1H and 13C nuclear magnetic resonance. The molecules were subjected to virtual screening and docking analysis against selected human molecular targets. Compound 5g displayed good binding properties as well as significant anticancer and DNA cleavage activity. Conclusion: Compound 5g has been identified as a potential lead candidate for further testing against additional cancer cell lines and animal models in future.

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Luedtke, Sherry A., Robert J. Kuhn, and Francis M. McCaffrey. "Pharmacologic Management of Supraventricular Tachycardias in Children." Annals of Pharmacotherapy 31, no. 10 (October 1997): 1227–43. http://dx.doi.org/10.1177/106002809703101016.

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OBJECTIVE: To review the literature regarding the use of antiarrhythmic agents in the management of Wolff-Parkinson-White (WPW) syndrome and atrioventricular nodal reentry tachycardia (AVNRT) in infants and children, and to discuss the advantages and disadvantages of specific agents in each arrhythmia in an effort to develop treatment guidelines. DATA SOURCES: A MEDLINE search encompassing the years 1966–1996 was used to identify pertinent literature for discussion. Additional references were found in the articles that were retrieved via MEDLINE. STUDY SELECTION: Clinical trials that address the use of antiarrhythmic agents for the treatment of the supraventricular tachycardias WPW and AVNRT in children were selected. Literature pertaining to dosage, pharmacokinetics, efficacy, and toxicity of antiarrhythmic agents in children were considered for possible inclusion in the review, and information judged to be pertinent by the authors was included in the discussion. DATA EXTRACTION: Although there are numerous reports of antiarrhythmic use in children, very few large studies are designed to evaluate an individual antiarrhythmic agent for a specific arrhythmia. Controlled, comparison trials of antiarrhythmic agents in children are virtually nonexistent. Ideally, controlled clinical trials are used to develop clinical guidelines; however, in this situation, most data and information must be obtained from case series of children treated. Although the results from these type of studies may be useful in developing guidelines for the optimal use of these agents, controlled trials are required for establishing standard treatment guidelines for all patients. DATA SYNTHESIS: Despite limited scientific evaluation of conventional agents in the treatment of WPW and AVNRT in children, they continue to be used as standard of care. Most information regarding the use of conventional agents in children has been extrapolated from the adult literature. Little justification for the use of the agents or dosing in children is available. Controlled trials regarding the use of new antiarrhythmic agents (propafenone, amiodarone, flecainide) are available; however, the variance in dosing schemes, presence of structural heart disease, and patient age make the development of recommendations difficult. CONCLUSIONS: Because of greater clinical experience with these conventional antiarrhythmic agents, they continue to be first-line therapy in the management of most supraventricular tachycardia (SVT) in children. The management of SVT in children with WPW syndrome should begin with the use of a β-blocker with the addition of digoxin or procainamide for treatment failures. The use of digoxin monotherapy, although frequently used by many practitioners in infants and children with WPW, cannot be recommended. For failures to conventional agents, flecainide is the preferred agent, while therapy with propafenone, amiodarone, and sotalol remains to be elucidated. The management of AVRNT is similar to that of WPW; however, digoxin is the agent of first choice. Trials of β-blockers and procainamide should follow for treatment failures with flecainide again being the preferred “newer” antiarrhythmic for use in resistant cases. Additional well-designed, controlled trials are needed to further evaluate the comparative efficacy of antiarrhythmics in the management of WPW and AVNRT in children, as well as to evaluate dosing and toxicity in various age groups.

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Bhattarai, Deepak, Muhammad Muddassar, Jae Jang, Seung Hong, Eunice Kim, Taegwon Oh, Sang-Nae Cho, Ae Pae, and Gyochang Keum. "Virtual Screening and Synthesis of Novel Antitubercular Agents Through Interaction-Based Pharmacophore and Molecular Docking Studies." Current Computer Aided-Drug Design 10, no. 4 (May 18, 2015): 383–92. http://dx.doi.org/10.2174/1573409911666150414150300.

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Bassetto, Marcella, Pieter Leyssen, Johan Neyts, Mark M. Yerukhimovich, David N. Frick, and Andrea Brancale. "Shape-based virtual screening, synthesis and evaluation of novel pyrrolone derivatives as antiviral agents against HCV." Bioorganic & Medicinal Chemistry Letters 27, no. 4 (February 2017): 936–40. http://dx.doi.org/10.1016/j.bmcl.2016.12.087.

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Nan, Jing, Shaoran Zhang, Ping Zhan, and Ling Jiang. "Discovery of Novel GMPS Inhibitors of Candidatus Liberibacter Asiaticus by Structure Based Design and Enzyme Kinetic." Biology 10, no. 7 (June 28, 2021): 594. http://dx.doi.org/10.3390/biology10070594.

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Citrus production is facing an unprecedented problem because of huanglongbing (HLB) disease. Presently, no effective HLB-easing method is available when citrus becomes infected. Guanosine 5′-monophosphate synthetase (GMPS) is a key protein in the de novo synthesis of guanine nucleotides. GMPS is used as an attractive target for developing agents that are effective against the patogen infection. In this research, homology modeling, structure-based virtual screening, and molecular docking were used to discover the new inhibitors against CLas GMPS. Enzyme assay showed that folic acid and AZD1152 showed high inhibition at micromole concentrations, with AZD1152 being the most potent molecule. The inhibition constant (Ki) value of folic acid and AZD1152 was 51.98 µM and 4.05 µM, respectively. These results suggested that folic acid and AZD1152 could be considered as promising candidates for the development of CLas agents.

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Karpina, Veronika R., Svitlana S. Kovalenko, Sergiy M. Kovalenko, Oleksandr G. Drushlyak, Natalya D. Bunyatyan, Victoriya A. Georgiyants, Vladimir V. Ivanov, Thierry Langer, and Louis Maes. "A Novel Series of [1,2,4]Triazolo[4,3-a]Pyridine Sulfonamides as Potential Antimalarial Agents: In Silico Studies, Synthesis and In Vitro Evaluation." Molecules 25, no. 19 (September 30, 2020): 4485. http://dx.doi.org/10.3390/molecules25194485.

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For the development of new and potent antimalarial drugs, we designed the virtual library with three points of randomization of novel [1,2,4]triazolo[4,3-a]pyridines bearing a sulfonamide fragment. The library of 1561 compounds has been investigated by both virtual screening and molecular docking methods using falcipain-2 as a target enzyme. 25 chosen hits were synthesized and evaluated for their antimalarial activity in vitro against Plasmodium falciparum. 3-Ethyl-N-(3-fluorobenzyl)-N-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide and 2-(3-chlorobenzyl)-8-(piperidin-1-ylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one showed in vitro good antimalarial activity with inhibitory concentration IC50 = 2.24 and 4.98 μM, respectively. This new series of compounds may serve as a starting point for future antimalarial drug discovery programs.

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Ramchuran, Estelle J., Isabel Pérez-Guillén, Linda A. Bester, René Khan, Fernando Albericio, Miguel Viñas, and Beatriz G. de la Torre. "Super-Cationic Peptide Dendrimers—Synthesis and Evaluation as Antimicrobial Agents." Antibiotics 10, no. 6 (June 10, 2021): 695. http://dx.doi.org/10.3390/antibiotics10060695.

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Microbial infections are a major public health concern. Antimicrobial peptides (AMPs) have been demonstrated to be a plausible alternative to the current arsenal of drugs that has become inefficient due to multidrug resistance. Herein we describe a new AMP family, namely the super-cationic peptide dendrimers (SCPDs). Although all members of the series exert some antibacterial activity, we propose that special attention should be given to (KLK)2KLLKLL-NH2 (G1KLK-L2KL2), which shows selectivity for Gram-negative bacteria and virtually no cytotoxicity in HepG2 and HEK293. These results reinforce the validity of the SCPD family as a valuable class of AMP and support G1KLK-L2KL2 as a strong lead candidate for the future development of an antibacterial agent against Gram-negative bacteria.

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Dev, Sanal, Sunil R. Dhaneshwar, and Bijo Mathew. "Virtual Combinatorial Library Design, Synthesis and In vitro Anticancer Assessment of -2-Amino-3-Cyanopyridine Derivatives." Combinatorial Chemistry & High Throughput Screening 21, no. 2 (April 17, 2018): 138–48. http://dx.doi.org/10.2174/1386207321666180228113925.

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Aim and Objective: For the development of new class of anticancer agents, a series of novel 2-amino-3-cyanopyridine derivatives were designed from virtual screening with Glide program by setting Topoisomerase II as the target. Materials and Methods: The top ranked ten molecules from the virtual screening were synthesized by microwave assisted technique and investigated for their cytotoxic activity against MCF-7 and A- 549 cell lines by using sulforhodamine B assay method. Results: The most active compound 2-amino-4-(3,5-dibromo-4-hydroxyphenyl)-6-(2,4- dichlorophenyl) nicotinonitrile (CG-5) showed significant cytotoxic profile with (LC50 = 97.1, TGI = 29.9 and GI50 = <0.1 µM) in MCF-7 and (LC50= 93.0, TGI= 50.0 and GI50= <7 µM) in A-549 cell lines. A molecular docking study was performed to explore the binding interaction of CG-5with the active site of Topoisomerase II. Conclusion: It can be concluded that halogen substituent pyridine ring was benefit for cytotoxicity.

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Stevanovic, Strahinja, Milan Sencanski, Mathieu Danel, Christophe Menendez, Roumaissa Belguedj, Abdelmalek Bouraiou, Katarina Nikolic, et al. "Synthesis, In Silico, and In Vitro Evaluation of Anti-Leishmanial Activity of Oxadiazoles and Indolizine Containing Compounds Flagged against Anti-Targets." Molecules 24, no. 7 (April 2, 2019): 1282. http://dx.doi.org/10.3390/molecules24071282.

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Due to the lack of approved vaccines against human leishmaniasis and the limitations of the current chemotherapy inducing side effects and drug resistance, development of new, effective chemotherapeutic agents is essential. This study describes the synthesis of a series of novel oxadiazoles and indolizine-containing compounds. The compounds were screened in silico using an EIIP/AQVN filter followed by ligand-based virtual screening and molecular docking to parasite arginase. Top hits were further screened versus human arginase and finally against an anti-target battery to tag their possible interactions with proteins essential for the metabolism and clearance of many substances. Eight candidate compounds were selected for further experimental testing. The results show measurable in vitro anti-leishmanial activity for three compounds. One compound with an IC50 value of 2.18 µM on Leishmania donovani intramacrophage amastigotes is clearly better positioned than the others as an interesting molecular template for further development of new anti-leishmanial agents.

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Debnath, Biplab, and Swastika Ganguly. "Synthesis, Biological Evaluation, in Silico Docking and Virtual ADME Studies of Novel Isatin Analogs as Promising Antimicrobial Agents." Anti-Infective Agents 13, no. 2 (October 29, 2015): 139–53. http://dx.doi.org/10.2174/2211352513666150714180118.

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Lande, Duc Hoàng, Abed Nasereddin, Arne Alder, Tim W. Gilberger, Ron Dzikowski, Johann Grünefeld, and Conrad Kunick. "Synthesis and Antiplasmodial Activity of Bisindolylcyclobutenediones." Molecules 26, no. 16 (August 5, 2021): 4739. http://dx.doi.org/10.3390/molecules26164739.

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Malaria is one of the most dangerous infectious diseases. Because the causative Plasmodium parasites have developed resistances against virtually all established antimalarial drugs, novel antiplasmodial agents are required. In order to target plasmodial kinases, novel N-unsubstituted bisindolylcyclobutenediones were designed as analogs to the kinase inhibitory bisindolylmaleimides. Molecular docking experiments produced favorable poses of the unsubstituted bisindolylcyclobutenedione in the ATP binding pocket of various plasmodial protein kinases. The synthesis of the title compounds was accomplished by sequential Friedel-Crafts acylation procedures. In vitro screening of the new compounds against transgenic NF54-luc P. falciparum parasites revealed a set of derivatives with submicromolar activity, of which some displayed a reasonable selectivity profile against a human cell line. Although the molecular docking studies suggested the plasmodial protein kinase PfGSK-3 as the putative biological target, the title compounds failed to inhibit the isolated enzyme in vitro. As selective submicromolar antiplasmodial agents, the N-unsubstituted bisindolylcyclobutenediones are promising starting structures in the search for antimalarial drugs, albeit for a rational development, the biological target addressed by these compounds has yet to be identified.

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Zhang, Beina, Mao Shu, Chunmei Xu, Chunhong An, Rui Wang, and Zhihua Lin. "Virtual Screening, Docking, Synthesis and Bioactivity Evaluation of Thiazolidinediones as Potential PPARγ Partial Agonists for Preparation of Antidiabetic Agents." Letters in Drug Design & Discovery 16, no. 6 (May 24, 2019): 608–17. http://dx.doi.org/10.2174/1570180815666180827123512.

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Background:Peroxisome proliferator-activated receptor gamma (PPARγ) is one of the key targets of insulin resistance research, in addition to being ligand-activated transcription factors of the nuclear hormone receptor superfamily with a leading role in adiposeness activation and insulin sensitivity. They regulate cholesterol and carbohydrate metabolism through direct actions on gene expression. Despite their therapeutic importance, there are dose limiting side effects associated with PPARγ drug treatments, thus a new generation of safer PPARγ drugs are being actively sought after treatment.Methods:In this study, we used computer aided drug design to screen new series of PPARγ ligands, and synthesized a series of potential thiazolidinedione derivatives such as 5,7- dibenzyloxybenzyl-3-hydroxymethyl-4H-coumarin-4-ketone, using 4-steps to synthesize the target compounds and built streptozotocin (STZ) induced insulin resistance rat model to measure their antidiabetic activity.Results:We found that 10 mg/kg concentration of compound 0701C could significantly decrease blood glucose and serum PPARγ, serum insulin levels in insulin resistance model rat.Conclusion:We would conclude that compound 0701C might serve as a potential PPARγ partial agonist.

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Derudas, Marco, Christophe Vanpouille, Davide Carta, Sonia Zicari, Graciela Andrei, Robert Snoeck, Andrea Brancale, Leonid Margolis, Jan Balzarini, and Christopher McGuigan. "Virtual Screening of Acyclovir Derivatives as Potential Antiviral Agents: Design, Synthesis, and Biological Evaluation of New Acyclic Nucleoside ProTides." Journal of Medicinal Chemistry 60, no. 18 (September 19, 2017): 7876–96. http://dx.doi.org/10.1021/acs.jmedchem.7b01009.

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Senaweera, Sameera, Haijuan Du, Huanchun Zhang, Karen A. Kirby, Philip R. Tedbury, Jiashu Xie, Stefan G. Sarafianos, and Zhengqiang Wang. "Discovery of New Small Molecule Hits as Hepatitis B Virus Capsid Assembly Modulators: Structure and Pharmacophore-Based Approaches." Viruses 13, no. 5 (April 27, 2021): 770. http://dx.doi.org/10.3390/v13050770.

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Hepatitis B virus (HBV) capsid assembly modulators (CpAMs) have shown promise as potent anti-HBV agents in both preclinical and clinical studies. Herein, we report our efforts in identifying novel CpAM hits via a structure-based virtual screening against a small molecule protein-protein interaction (PPI) library, and pharmacophore-guided compound design and synthesis. Curated compounds were first assessed in a thermal shift assay (TSA), and the TSA hits were further evaluated in an antiviral assay. These efforts led to the discovery of two structurally distinct scaffolds, ZW-1841 and ZW-1847, as novel HBV CpAM hits, both inhibiting HBV in single-digit µM concentrations without cytotoxicity at 100 µM. In ADME assays, both hits displayed extraordinary plasma and microsomal stability. Molecular modeling suggests that these hits bind to the Cp dimer interfaces in a mode well aligned with known CpAMs.

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Li, Huan, Na Yang, Lixia Xiong, and Baolei Wang. "Design, Synthesis and Biological Evaluation of Novel Thienylpyridyl- and Thioether-Containing Acetamides and Their Derivatives as Pesticidal Agents." Molecules 26, no. 18 (September 17, 2021): 5649. http://dx.doi.org/10.3390/molecules26185649.

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Referring to the structural information of the “hit” compound A from the reported pharmacophore-based virtual screening, a series of novel thienylpyridyl- and thioether/sulfoxide/sulfone-containing acetamide derivatives have been designed and synthesized. The structures of new compounds were confirmed by 1H NMR, 13C NMR and HRMS. The single-crystal structure of A was firstly reported. All the new synthesized compounds were evaluated for insecticidal activities on Mythimna separata Walker and Plutella xylostella L. Through a step-by-step structural optimization, the high insecticidal agents, especially towards Plutella xylostella L., have been found, and thienylpyridyl- and sulfone/thioether-containing acetamides Iq, Io, Ib and A, which are comparable with the control insecticides cartap, triflumuron and chlorantraniliprole in the present study, can be used as novel lead structures for new insecticides innovation research. In addition, some of the compounds, e.g., A, Ih, Id, Io and Iq, also exhibited favourable fungicidal activities against Physalospora piricola, Rhizoctonia cerealis and Sclerotinia sclerotiorum and would provide useful guidance for the design and development of new fungicides.

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Hariyanti, Hariyanti, Kusmadi Kurmardi, Arry Yanuar, and Hayun Hayun. "Ligand Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies of Asymmetrical Hexahydro-2H-Indazole Analogs of Curcumin (AIACs) to Discover Novel Estrogen Receptors Alpha (ERα) Inhibitor." Indonesian Journal of Chemistry 21, no. 1 (November 26, 2020): 137. http://dx.doi.org/10.22146/ijc.54745.

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The estrogen receptor alpha (ERα) plays an important role in breast development and pro-proliferation signal activation in the normal and cancerous breast. The ERα inhibitors were potentially active as cytotoxic agents against breast cancer. This study was conducted in order to find Asymmetrical Hexahydro-2H-Indazole Analogs of Curcumin (AIACs) as hits of ERα inhibitor. A training set of 17 selected ERα inhibitors was used to create 10 pharmacophore models using LigandScout 4.2. The pharmacophore models were validated using 383 active compounds as positive data and 20674 decoys as negative data obtained from DUD.E. Model 2 was found as the best pharmacophore model and consisted of three types of pharmacophore features, viz. one hydrophobic, one hydrogen bond acceptor, and aromatic interactions. Model 2 was utilized for ligand-based virtual screening 186 of AIACs, AMACs, intermediates, and Mannich base derivative compounds. The hits obtained were further screened using molecular docking, analyzed using drug scan, and tested for its synthesis accessibility. Fourteen compounds were fulfilled as hits in pharmacophore modeling, in which 10 hits were selected by molecular docking, but only seven hits met Lipinski’s rule of five and had medium synthesis accessibility. In conclusion, seven compounds were suggested to be potentially active as ERα inhibitors and deserve to be synthesized and further investigated.

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Luo, Tiffany Christina, Adrian Aguilera, Courtney Rees Lyles, and Caroline Astrid Figueroa. "Promoting Physical Activity Through Conversational Agents: Mixed Methods Systematic Review." Journal of Medical Internet Research 23, no. 9 (September 14, 2021): e25486. http://dx.doi.org/10.2196/25486.

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Background Regular physical activity (PA) is crucial for well-being; however, healthy habits are difficult to create and maintain. Interventions delivered via conversational agents (eg, chatbots or virtual agents) are a novel and potentially accessible way to promote PA. Thus, it is important to understand the evolving landscape of research that uses conversational agents. Objective This mixed methods systematic review aims to summarize the usability and effectiveness of conversational agents in promoting PA, describe common theories and intervention components used, and identify areas for further development. Methods We conducted a mixed methods systematic review. We searched seven electronic databases (PsycINFO, PubMed, Embase, CINAHL, ACM Digital Library, Scopus, and Web of Science) for quantitative, qualitative, and mixed methods studies that conveyed primary research on automated conversational agents designed to increase PA. The studies were independently screened, and their methodological quality was assessed using the Mixed Methods Appraisal Tool by 2 reviewers. Data on intervention impact and effectiveness, treatment characteristics, and challenges were extracted and analyzed using parallel-results convergent synthesis and narrative summary. Results In total, 255 studies were identified, 7.8% (20) of which met our inclusion criteria. The methodological quality of the studies was varied. Overall, conversational agents had moderate usability and feasibility. Those that were evaluated through randomized controlled trials were found to be effective in promoting PA. Common challenges facing interventions were repetitive program content, high attrition, technical issues, and safety and privacy concerns. Conclusions Conversational agents hold promise for PA interventions. However, there is a lack of rigorous research on long-term intervention effectiveness and patient safety. Future interventions should be based on evidence-informed theories and treatment approaches and should address users’ desires for program variety, natural language processing, delivery via mobile devices, and safety and privacy concerns.

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Duke, Stephen O. "Herbicide and Pharmaceutical Relationships." Weed Science 58, no. 3 (September 2010): 334–39. http://dx.doi.org/10.1614/ws-09-102.1.

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For many years, virtually all pharmaceutical companies had an agrochemical division. This was partly to maximize the benefits of expensive chemical synthesis efforts by searching for many types of useful biological activities. Leads for pharmaceuticals and pesticides often overlap, in some cases leading to similar compounds used for human health and weed management purposes. This review will focus on herbicides and herbicide classes that have potential pharmaceutical properties, both as therapeutic agents that act through human molecular target sites and those that act on infectious agents. An example of the first case is compounds that target plant acetyl coenzyme A carboxylases, inhibiting fatty acid synthesis, and similar compounds used in humans as anti-inflammatory agents. Another such example is the triketone class of compounds that can act both as herbicides and as treatments for the genetic disease tyrosinemia, targeting the same enzyme in both cases. Examples of the second case are the relatively large number of herbicides that have activity against the malaria protozoan (Plasmodiumspp.). It turns out thatPlasmodiumspp. and related disease organisms have an organelle that is apparently analogous to the plant plastid, the apicoplast. Herbicides such as dinitroanilines are active against several protozoan parasites by the same mechanism by which they kill plants, interaction with tubulin to halt cell division and other tubulin-dependent processes. These and other multiple activities of various herbicides and herbicide classes provide perspective on the broad biological activity of herbicides and related compounds.

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Chalenko, Natalya Mykolaivna, Anna Olegovna Syrovaya, Natalya P. Kobzar, Maryna V. Rakhimova, Irina A. Sych, and Igor Vladimirovich Sych. "Prediction of the Antiinflammatory Activity of New S-alkyl Derivatives of 1,2,4-triazol-3-thiones Using the PASS Computer Program and Molecular Docking." Borneo Journal of Pharmacy 3, no. 1 (February 27, 2020): 36–43. http://dx.doi.org/10.33084/bjop.v3i1.1082.

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The strategy of rational approaches to the search for selective COX-2 inhibitors as potential antiinflammatory agents has been proposed and elaborated. It is based on the use of PASS-prediction and molecular docking. The choice of the basic structure of 4-amino-3-thio-1,2,4-triazole as a promising object of chemical modification has been substantiated. Using a modification of the primary molecule, a virtual library of S-derivatives of 5-substituted 4-amino(pyrrol)3-thio-4H-1,2,4-triazoles in the amount of 100 compounds (ten groups) has been obtained by introducing various pharmacophore fragments. Based on the analysis of the results of the PASS-prediction and molecular docking, six of the ten planned groups of compounds have been selected for the synthesis as promising selective COX-2 inhibitors. The reliability of the prediction results has already been confirmed for one of the promising group 4-amino-5-(pyridine-4-yl)-1,2,4-triazole (4?)-3-yl-thioacetamides.

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Aronov, Alex M., Narsimha R. Munagala, Irwin D. Kuntz, and Ching C. Wang. "Virtual Screening of Combinatorial Libraries across a Gene Family: in Search of Inhibitors of Giardia lamblia Guanine Phosphoribosyltransferase." Antimicrobial Agents and Chemotherapy 45, no. 9 (September 1, 2001): 2571–76. http://dx.doi.org/10.1128/aac.45.9.2571-2576.2001.

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ABSTRACT Parasitic protozoa lack the ability to synthesize purine nucleotides de novo, relying instead on purine salvage enzymes for their survival. Guanine phosphoribosyltransferase (GPRT) from the protozoan parasite Giardia lamblia is a potential target for rational antiparasitic drug design, based on the experimental evidence, which indicates the lack of interconversion between adenine and guanine nucleotide pools. The present study is a continuation of our efforts to use three-dimensional structures of parasitic phosphoribosyltransferases (PRTs) to design novel antiparasitic agents. Two micromolar phthalimide-based GPRT inhibitors were identified by screening the in-house phthalimide library. A combination of structure-based scaffold selection using virtual library screening across the PRT gene family and solid phase library synthesis led to identification of smaller (molecular weight, <300) ligands with moderate to low specificity for GPRT; the best inhibitors, GP3 and GP5, had K i values in the 23 to 25 μM range. These results represent significant progress toward the goal of designing potent inhibitors of purine salvage inGiardia parasites. As a second step in this process, altering the phthalimide moiety to optimize interactions in the guanine-binding pocket of GPRT is expected to lead to compounds with promising activity against G. lamblia PRT.

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Vernieri, Ermelinda, Isabel Gomez-Monterrey, Ciro Milite, Paolo Grieco, Simona Musella, Alessia Bertamino, Ilaria Scognamiglio, et al. "Design, Synthesis, and Evaluation of New Tripeptides as COX-2 Inhibitors." Journal of Amino Acids 2013 (February 26, 2013): 1–7. http://dx.doi.org/10.1155/2013/606282.

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Cyclooxygenase (COX) is a key enzyme in the biosynthetic pathway leading to the formation of prostaglandins, which are mediators of inflammation. It exists mainly in two isoforms COX-1 and COX-2. The conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have gastrointestinal side effects because they inhibit both isoforms. Recent data demonstrate that the overexpression of these enzymes, and in particular of cyclooxygenases-2, promotes multiple events involved in tumorigenesis; in addition, numerous studies show that the inhibition of cyclooxygenases-2 can delay or prevent certain forms of cancer. Agents that inhibit COX-2 while sparing COX-1 represent a new attractive therapeutic development and offer a new perspective for a further use of COX-2 inhibitors. The present study extends the evaluation of the COX activity to all 203 possible natural tripeptide sequences following a rational approach consisting in molecular modeling, synthesis, and biological tests. Based on data obtained from virtual screening, only those peptides with better profile of affinity have been selected and classified into two groups called S and E. Our results suggest that these novel compounds may have potential as structural templates for the design and subsequent development of the new selective COX-2 inhibitors drugs.

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Raghava Doonaboyina, Abhilasha Mittal, and Sridhar Babu Gummadi. "Docking, Screening, Synthesis of 4-hydroxy-6-methyl-2-phenyl-1-benzofuran-3(2H)-one derivatives as new leads for anti-cancer activity." International Journal of Research in Pharmaceutical Sciences 10, no. 2 (April 15, 2019): 883–95. http://dx.doi.org/10.26452/ijrps.v10i2.271.

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Auroneis a bicyclic ring where a benzene ring fused with a furanone. Docking is an efficient tool in the development of new lead molecules. Docking, virtual screening, ADMET prediction are prominent devices in the identification of new lead molecules. Synthetic chemistry plays a major in developing a series of potent anti-cancer agents. Benzofuranone was synthesized by reacting benzene diols, and triols with bromo phenyl acetonitrile yielded an imine derivative are converted to a ketone with treatment with hydrochloric acid then cyclised with sodium acetate. The compounds identity and purity were confirmed by spectral and analytical methods. Benzofuranone derivatives are screened antineoplastic activity was performed against human skin cancer cell line G361 at micro molecular concentrations. The compound IIIA was found to be with potent activity.

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Raghava Doonaboyina, Abhilasha Mittal, and Sridhar Babu Gummadi. "Computational design, Synthesis of 4,6-dihydroxy-2-phenyl-1-benzofuran-3(2H)-one derivatives as new leads for anti-cancer activity." International Journal of Research in Pharmaceutical Sciences 10, no. 2 (April 15, 2019): 896–908. http://dx.doi.org/10.26452/ijrps.v10i2.273.

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Benzofuranone is a bicyclic ring where a benzene ring fused with a furanone. Computation chemistry plays a major role in the development of new lead molecules. Computational tools docking, virtual screening, ADMET prediction are utilised in the identification of new lead molecules. Synthetic chemistry plays a major in developing a series of potent anti-cancer agents. Benzofuranone was synthesized by reacting benzene diols, and triols with bromo phenyl acetonitrile yielded an imine derivative are converted to a ketone with treatment with hydrochloric acid then cyclised with sodium acetate. The compounds identity and purity were confirmed by spectral and analytical methods. Benzofuranone derivatives are screened antineoplastic activity was performed against human skin cancer cell line G361 at micro molecular concentrations. The compounds IA, IB, ID, IE, IF, was found to be with potent activity.

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Gatti, Giorgio, Mina Errahali, Lorenzo Tei, Enzo Mangano, Stefano Brandani, Maurizio Cossi, and Leonardo Marchese. "A Porous Carbon with Excellent Gas Storage Properties from Waste Polystyrene." Nanomaterials 9, no. 5 (May 10, 2019): 726. http://dx.doi.org/10.3390/nano9050726.

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In this paper, we describe the synthesis and gas adsorption properties of a porous carbonaceous material, obtained from commercial expanded polystyrene. The first step consists of the Friedel-Craft reaction of the dissolved polystyrene chains with a bridging agent to form a highly-crosslinked polymer, with permanent porosity of 0.7 cm3/g; then, this polymer is treated with potassium hydroxide at a high temperature to produce a carbon material with a porous volume larger than 1.4 cm3/g and a distribution of ultramicro-, micro-, and mesopores. After characterization of the porous carbon and determination of the bulk density, the methane uptake was measured using a volumetric apparatus to pressures up to 30 bar. The equilibrium adsorption isotherm obtained is among the highest ever reported for this kind of material. The interest of this product lies both in its excellent performance and in the virtually costless starting material.

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Ruvolo, Peter P., Fengqin Gao, William L. Blalock, Xingming Deng, and W. Stratford May. "Ceramide Regulates Protein Synthesis by a Novel Mechanism Involving the Cellular PKR Activator RAX." Journal of Biological Chemistry 276, no. 15 (January 8, 2001): 11754–58. http://dx.doi.org/10.1074/jbc.m011400200.

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The sphingolipid ceramide is an important second signal molecule and potent apoptotic agent. The production of ceramide is associated with virtually every known stress stimulus, and thus, generation of this sphingolipid has been suggested as a universal feature of apoptosis. Recent studies suggest that an important component of cell death following diverse stress stimuli (e.g. interleukin-3 withdrawal, sodium arsenite treatment, and peroxide treatment) is the activation of the double-stranded RNA-activable protein kinase, PKR, resulting in the inhibition of protein synthesis (Ito, T., Jagus, R., and May, W. S. (1994)Proc. Natl. Acad. Sci. U. S. A.91, 7455–7459). The recently discovered cellular PKR activator, RAX, is phosphorylated in association with PKR activation (Ito, T., Yang, M., and May, W. S. (1999)J. Biol. Chem.274, 15427–15432). Since RAX is phosphorylated by an as yet undetermined SAPK and ceramide is a potent activator of SAPKs such as JNK, a role for ceramide in the activation of RAX might be possible. Results indicate that overexpression of exogenous RAX potentiates ceramide-induced killing. Furthermore, ceramide can potently inhibit protein synthesis. Since ceramide potently promotes RAX and eukaryotic initiation factor-2α phosphorylation, a possible role for ceramide in this process may involve the activation of PKR by RAX. Since 2-aminopurine, a serine/threonine kinase inhibitor that has previously been shown to inhibit PKR, blocks both the potentiation of ceramide killing by RAX and ceramide-induced inhibition of protein synthesis, ceramide appears to promote PKR activation, at least indirectly. Collectively, these findings suggest a novel role for ceramide in the regulation of protein synthesis and apoptosis.

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Di Cristo, Francesca, Anna Calarco, Filomena Anna Digilio, Maria Stefania Sinicropi, Camillo Rosano, Umberto Galderisi, Mariarosa Anna Beatrice Melone, Carmela Saturnino, and Gianfranco Peluso. "The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure-Based Virtual Screening to In Vivo Biological Activity." International Journal of Molecular Sciences 21, no. 19 (October 8, 2020): 7431. http://dx.doi.org/10.3390/ijms21197431.

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A mismatch between β-oxidation and the tricarboxylic acid cycle (TCA) cycle flux in mitochondria produces an accumulation of lipid metabolic intermediates, resulting in both blunted metabolic flexibility and decreased glucose utilization in the affected cells. The ability of the cell to switch to glucose as an energy substrate can be restored by reducing the reliance of the cell on fatty acid oxidation. The inhibition of the carnitine system, limiting the carnitine shuttle to the oxidation of lipids in the mitochondria, allows cells to develop a high plasticity to metabolic rewiring with a decrease in fatty acid oxidation and a parallel increase in glucose oxidation. We found that 3-(2,2,2-trimethylhydrazine)propionate (THP), which is able to reduce cellular carnitine levels by blocking both carnitine biosynthesis and the cell membrane carnitine/organic cation transporter (OCTN2), was reported to improve mitochondrial dysfunction in several diseases, such as Huntington’s disease (HD). Here, new THP-derived carnitine-lowering agents (TCL), characterized by a high affinity for the OCTN2 with a minimal effect on carnitine synthesis, were developed, and their biological activities were evaluated in both in vitro and in vivo HD models. Certain compounds showed promising biological activities: reducing protein aggregates in HD cells, ameliorating motility defects, and increasing the lifespan of HD Drosophila melanogaster.

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Goldin, Daniel S., Samuel L. Venneri, and Ahmed K. Noor. "Ready for the Future?" Mechanical Engineering 121, no. 11 (November 1, 1999): 61–66. http://dx.doi.org/10.1115/1.1999-nov-2.

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The potential benefits for product development and scientific research have led many organizations to initiate programs to design collaborative distributed virtual environments. The goal of NASA's programs, Intelligent Synthesis Environment (ISE) and Intelligent Systems (IS), is to revolutionize scientific research and engineering processes by creating a distributed collaborative environment that will enable the linking of design teams and scientists from NASA, industry, and universities in the creation and operation of aerospace systelT1S and in synthesizing their missions. The programs' broad framework also will be used for scientific research and product development in complex non-aerospace applications. The advent of intelligent agents, which enabled the learner to manipulate cognitive artifacts from several perspectives or viewpoints, led to the interactive learning systems of the 1990s. The contributions of ISE and IS can be incorporated into three categories of advanced learning environments: expert-led group learning; self-paced individual learning; and collaborative learning; which, in combination, can reduce the time and cost of learning, and sustain and increase worker competencies in engineering organizations.

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Hasipek, Metis, Dale Grabowski, Yihong Guan, James G. Phillips, Jaroslaw P. Maciejewski, Hetty E. Carraway, and Babal K. Jha. "Targeting Antagonists of Retinoic Acid Signaling in Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 4067. http://dx.doi.org/10.1182/blood-2018-99-118924.

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Abstract Introduction: Retinoic acid (RA), the active metabolite of vitamin A, influences biological processes by activating the retinoic acid receptor (RAR). RARs are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate homeostasis of cellular growth. The success of RAR modulation in the treatment of acute promyelocytic leukemia (APL) particularly by the use of all-trans retinoic acid (ATRA) has stimulated considerable interest in the development of small molecules that can modulate RAR and RXR. Recent studies have demonstrated that RA can also activate the peroxisome proliferator-activated receptor β/δ (PPARβ/δ). In the aqueous intracellular milieu, RA is transported by the cellular retinoid-binding protein CRABP-II, or by the fatty-acid-binding protein FABP5, depending on the ratio of FABP5 to CRABP-II. In cells expressing high CRABP-II and low FABP5, RA activates the RAR, whereas in the presence of the reverse ratio, RA activates PPARβ/δ (Fig 1). These two different modes of RA delivery due to the different ratio of these two cargos leads to opposite cellular outcomes. Cells harboring high level of CRABP-II, RA is delivered to RAR leading to apoptosis, growth arrest, and anticancer activity. However, when FABP5 expression is high, RA is delivered to PPARβ/δ resulting in survival, proliferation, and tumor growth. In both cases, retinoid X receptor (RXR) is the indispensable partner of the nuclear receptor involved. Therefore, preventing FABP5 from such antagonism may be a novel therapeutic strategy for AML. Here we report the development of a therapeutic strategy based on a highly specific FABP5 inhibitor (iFABP5) (Fig 2) that will allow the delivery of RA by CRABP-II to activate tumor suppressor function of RAR and RXR. Methods: An iterative approach of design synthesis and activity were employed to select the most potent hit, iFABP5, for further experiments. Expression levels were analyzed by western blot analysis and qRT-PCR. Colony forming assays were used to analyze iFABP5 activity against AML cell lines. Flow cytometry based cell differentiation assay were performed to assess the efficacy of iFABP5 and ATRA combination treatment. Results: The analysis of TCGA data set revealed that a certain class of AML patients (pts) (Trisomy 8 AML) have low levels of CRABP-II and high levels of FABP5, presumably due to gene duplication, that in part explains the inability of ATRA to induce terminal differentiation in AML cells. To test our hypothesis, we screened AML and APL patient (pt) bone marrow cells and found that a number of AML pts bone marrow have high FABP5 and low CRABP-II protein levels while the ATRA responding APL pts has opposite ratio determined by western blotting. Therefore, low CRABP-II and high FABP5 levels in a subset of AML pts lead to the activation of pro-survival PPARβ/δ pathway that promotes proliferation and opposes the differentiation. We also analyzed AML and APL pt samples along with different AML cell lines for mRNA expression using qRT-PCR. High FABP5 levels were observed in the majority of the AML cell lines. Efficacy of novel small molecule FABP5 inhibitor as a single agent and in combination with ATRA was evaluated in HL-60 cells. The FABP5 inhibitor iFABP5 was found to increase differentiation at 72 hours as assessed by both CD11b and CD14 levels in HL-60 cells. To confirm that iFABP5 is targeting FABP5 and indirectly targeting the PPARβ/δ pathway, levels of RAR and PPARβ/δ target genes were evaluated in the absence and presence of iFABP5. Changes in the gene expression of RAR and PPARβ/δ target genes in the presence and absence of iFABP5 were also examined in shFABP5, shPPARβ/δ, and shCRABP2 versus wild type cells. Conclusion: We demonstrated that a small molecule inhibitor of FABP5 synergizes with ATRA and induces the differentiation in AML cells. High FABP5 levels (mRNA and protein) were observed in the majority of the AML cell lines. Hence, FABP5 can be a therapeutic target in AML. Utilizing virtual screening and structurally guided design, we developed a small molecule FABP5 inhibitor that induces monocytic differentiation as observed by increased CD14 surface expression as a single agent and in combination with ATRA. FABP5 is not only a strong target to treat AML pts but also an excellent approach for developing a novel therapeutic for pts where FABP5 expression and activity is high. Disclosures Maciejewski: Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy. Carraway:Agios: Consultancy, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; FibroGen: Consultancy; Jazz: Speakers Bureau; Novartis: Speakers Bureau.

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Fuchter, Matthew J., Chang Zhong, Hong Zong, Brian M. Hoffman, and Anthony G. M. Barrett. "Porphyrazines: Designer Macrocycles by Peripheral Substituent Change." Australian Journal of Chemistry 61, no. 4 (2008): 235. http://dx.doi.org/10.1071/ch07445.

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It is rare that such a diverse array of applications can be realized from a single basic molecular unit, however, such is the power of the tetrapyrrolic macrocycle motif. Indeed, their potential in areas such as chemical dyes, optical sensors, optoelectronics, and biomedical agents is a function of their rich electronic and optical properties. While the naturally occurring porphyrins and the synthetic phthalocyanines have been extensively studied, the related tetraazaporphyrins or porphyrazines remain comparatively underdeveloped. Since porphyrazines maintain a unique position in this family: analogous derivatives are virtually inaccessible for the porphyrins, and direct fusion of heteroatomic substituents onto the porphyrazine β-positions results in a more pronounced effect compared with the substitution of an equivalent group onto the benzenoid rings of the phthalocyanine; a driving force exists to further explore the synthesis and applications of these novel macrocycles. This review will provide a historical overview of the synthetic strategies towards functionalized porphyrazines and describe new strategies towards the preparation and applications of heteroatom-appended porphyrazines, particularly in the context of their multimetallic complexes, catalysis, surface chemistry, and as biomedical agents.

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Journal articles on the topic 'Virtual agent synthesis'

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