Journal articles: 'Co-crystal screening'

1

Springuel, Géraldine, Bernadette Norberg, Koen Robeyns, Johan Wouters, and Tom Leyssens. "Advances in Pharmaceutical Co-crystal Screening: Effective Co-crystal Screening through Structural Resemblance." Crystal Growth & Design 12, no. 1 (November 30, 2011): 475–84. http://dx.doi.org/10.1021/cg201291k.

Full text

APA, Harvard, Vancouver, ISO, and other styles

2

Aakeröy, Christer B., Angela B. Grommet, and John Desper. "Co-Crystal Screening of Diclofenac." Pharmaceutics 3, no. 3 (August 31, 2011): 601–14. http://dx.doi.org/10.3390/pharmaceutics3030601.

Full text

APA, Harvard, Vancouver, ISO, and other styles

3

Veith, Heiner, Miko Schleinitz, Carsten Schauerte, and Gabriele Sadowski. "Thermodynamic Approach for Co-crystal Screening." Crystal Growth & Design 19, no. 6 (May 10, 2019): 3253–64. http://dx.doi.org/10.1021/acs.cgd.9b00103.

Full text

APA, Harvard, Vancouver, ISO, and other styles

4

Rahman, Fatinah Ab, Syarifah Abd Rahim, C. Tan Chou, Souk H. Low, and Noor Ashila Ramle. "Carbamazepine-Fumaric Acid and Carbamazepine-Succinic Acid Co-crystal Screening Using Solution Based Method." International Journal of Chemical Engineering and Applications 8, no. 2 (April 2017): 136–40. http://dx.doi.org/10.18178/ijcea.2017.8.2.645.

Full text

APA, Harvard, Vancouver, ISO, and other styles

5

Othman, Muhamad Fitri, Norasikin Jamburi, Nornizar Anuar, Syarifah Abd. Rahim, and Nurul Hazwani Rohalim. "Ibuprofen-Amino Acids Co-Crystal Screening Via Co-Grinding Methods." MATEC Web of Conferences 69 (2016): 03002. http://dx.doi.org/10.1051/matecconf/20166903002.

Full text

APA, Harvard, Vancouver, ISO, and other styles

6

Abd Hashib, Syafiza, Nornizar Anuar, Norasikin Jamburi, Nur Fazizi Ahmad, and Syarifah Abd Rahim. "Screening for Ibuprofen-Sachharin Co-Crystal Formation in Wet Milling." Applied Mechanics and Materials 754-755 (April 2015): 1002–6. http://dx.doi.org/10.4028/www.scientific.net/amm.754-755.1002.

Full text

Abstract:

Co-crystallization process has been used in pharmaceutical industry in producing new class of API solids due to its advantages such as physical stability and solubility.The objective of this study is to characterize the co-crystal formation of ibuprofen with saccharin as a co-crystal former through wet milling by using XRD, FTIR and DSC. A study of co-crystal formation from ibuprofen and saccharin has been conducted by using wet milling with the presence of solvent. The PXRD results showed a new phase which is believed a new crystalline has been successfully formed. The DSC analysis showed a new melting point for the new phase. However, the functional group assessment showed the presence of an unknown functional group in the system.

APA, Harvard, Vancouver, ISO, and other styles

7

Hoxha, Kreshnik, David H. Case, Graeme M. Day, and Timothy J. Prior. "Co-crystallisation of cytosine with 1,10-phenanthroline: computational screening and experimental realisation." CrystEngComm 17, no. 37 (2015): 7130–41. http://dx.doi.org/10.1039/c5ce01286d.

Full text

Abstract:

Crystal structure prediction calculations applied to co-crystals of 1,10-phenanthroline and nucleobases (A, T, C, G) show that only cytosine is expected to form a 1 : 1 co-crystal. Experiments provide verification for this result although the observed co-crystal crystallises with Z′ = 2, not Z′ = 1.

APA, Harvard, Vancouver, ISO, and other styles

8

Zhang, Geoff G. Z., Rodger F. Henry, Thomas B. Borchardt, and Xiaochun Lou. "Efficient Co-crystal Screening Using Solution-Mediated Phase Transformation." Journal of Pharmaceutical Sciences 96, no. 5 (May 2007): 990–95. http://dx.doi.org/10.1002/jps.20949.

Full text

APA, Harvard, Vancouver, ISO, and other styles

9

Veith, Heiner, Christian Luebbert, Naír Rodríguez-Hornedo, and Gabriele Sadowski. "Co-Crystal Screening by Vapor Sorption of Organic Solvents." Crystal Growth & Design 21, no. 8 (June 9, 2021): 4445–55. http://dx.doi.org/10.1021/acs.cgd.1c00355.

Full text

APA, Harvard, Vancouver, ISO, and other styles

10

Wicker, Jerome G. P., Lorraine M. Crowley, Oliver Robshaw, Edmund J. Little, Stephen P. Stokes, Richard I. Cooper, and Simon E. Lawrence. "Will they co-crystallize?" CrystEngComm 19, no. 36 (2017): 5336–40. http://dx.doi.org/10.1039/c7ce00587c.

Full text

APA, Harvard, Vancouver, ISO, and other styles

11

Abd Rahim, Syarifah, Nurul Aini Rosli, and Siti Salasiah Mohd Khalid. "Screening of Carbamazepine-Ibuprofen Co-Crystal Formation Using Non-Stoichiometric and Stoichiometric Methods." Advanced Materials Research 1113 (July 2015): 417–21. http://dx.doi.org/10.4028/www.scientific.net/amr.1113.417.

Full text

Abstract:

The paper presents the co-crystal screening study of carbamazepine (CBZ) and ibuprofen (IBU) as a co-crystal former (CCF) using non-stoichiometric (solid addition of CBZ to saturated solution of co-crystal former (CCF) and stoichiometric (1:1 mol of CBZ and CCF) methods. In the non-stoichiometric method, CBZ-IBU co-crystal was prepared in various solvents and left to equilibrate in three conditions; stagnant, manually agitated and shaking in 72 hours whereas in the stoichiometric method, evaporation, solvent drop grinding and dry grinding were used. The crystals produced from the screening process were characterized using differential scanning calorimetry (DSC) and optical microscopy. The co-crystal of CBZ-IBU was found to have successfully formed via the non-stoichiometric method in formic acid. DSC analysis revealed that the remaining crystals produced were either CBZ or IBU as indicated by their respective melting point.

APA, Harvard, Vancouver, ISO, and other styles

12

Abd Rahim, Syarifah, Chou Choang Tan, and Noor Ashila Ramle. "Carbamazepine-Fumaric Acid Co-Crystal Screening Using Solution Based Method." MATEC Web of Conferences 69 (2016): 03003. http://dx.doi.org/10.1051/matecconf/20166903003.

Full text

APA, Harvard, Vancouver, ISO, and other styles

13

Parker, Lorien J., Shigenao Taruya, Keiko Tsuganezawa, Naoko Ogawa, Junko Mikuni, Keiko Honda, Yuri Tomabechi, et al. "Kinase crystal identification and ATP-competitive inhibitor screening using the fluorescent ligand SKF86002." Acta Crystallographica Section D Biological Crystallography 70, no. 2 (January 29, 2014): 392–404. http://dx.doi.org/10.1107/s1399004713028654.

Full text

Abstract:

The small kinase inhibitor SKF86002 lacks intrinsic fluorescence but becomes fluorescent upon binding to the ATP-binding sites of p38 mitogen-activated protein kinase (p38α). It was found that co-crystals of this compound with various kinases were distinguishable by their strong fluorescence. The co-crystals of SKF86002 with p38α, Pim1, ASK1, HCK and AMPK were fluorescent. Addition of SKF86002, which binds to the ATP site, to the co-crystallization solution of HCK promoted protein stability and thus facilitated the production of crystals that otherwise would not grow in the apo form. It was further demonstrated that the fluorescence of SKF86002 co-crystals can be applied to screen for candidate kinase inhibitors. When a compound binds competitively to the ATP-binding site of a kinase crystallized with SKF86002, it displaces the fluorescent SKF86002 and the crystal loses its fluorescence. Lower fluorescent signals were reported after soaking SKF86002–Pim1 and SKF86002–HCK co-crystals with the inhibitors quercetin, a quinazoline derivative and A-419259. Determination of the SKF86002–Pim1 and SKF86002–HCK co-crystal structures confirmed that SKF86002 interacts with the ATP-binding sites of Pim1 and HCK. The structures of Pim1–SKF86002 crystals soaked with the inhibitors quercetin and a quinazoline derivative and of HCK–SKF86002 crystals soaked with A-419259 were determined. These structures were virtually identical to the deposited crystal structures of the same complexes. A KINOMEscanassay revealed that SKF86002 binds a wide variety of kinases. Thus, for a broad range of kinases, SKF86002 is useful as a crystal marker, a crystal stabilizer and a marker to identify ligand co-crystals for structural analysis.

APA, Harvard, Vancouver, ISO, and other styles

14

Wünsche, Steffi, Lina Yuan, Andreas Seidel-Morgenstern, and Heike Lorenz. "A Contribution to the Solid State Forms of Bis(demethoxy)curcumin: Co-Crystal Screening and Characterization." Molecules 26, no. 3 (January 30, 2021): 720. http://dx.doi.org/10.3390/molecules26030720.

Full text

Abstract:

Bis(demethoxy)curcumin (BDMC) is one of the main active components found in turmeric. Major drawbacks for its usage are its low aqueous solubility, and the challenging separation from other curcuminoids present in turmeric. Co-crystallization can be applied to alter the physicochemical properties of BDMC in a desired manner. A co-crystal screening of BDMC with four hydroxybenzenes was carried out using four different methods of co-crystal production: crystallization from solution by slow solvent evaporation (SSE), and rapid solvent removal (RSR), liquid-assisted grinding (LAG), and crystallization from the melt phase. Two co-crystal phases of BDMC were obtained with pyrogallol (PYR), and hydroxyquinol (HYQ). PYR-BDMC co-crystals can be obtained only from the melt, while HYQ-BDMC co-crystals could also be produced by LAG. Both co-crystals possess an equimolar composition and reveal an incongruent melting behavior. Infrared spectroscopy demonstrated the presence of BDMC in the diketo form in the PYR co-crystals, while it is in a more stable keto-enol form in the HYQ co-crystals. Solubility measurements in ethanol and an ethanol-water mixture revealed an increase of solubility in the latter, but a slightly negative effect on ethanol solubility. These results are useful for a prospective development of crystallization-based separation processes of chemical similar substances through co-crystallization.

APA, Harvard, Vancouver, ISO, and other styles

15

Klamt, A. "Co-crystal screening and other potential applications of COSMO-RS for crystallography." Acta Crystallographica Section A Foundations of Crystallography 69, a1 (August 25, 2013): s152. http://dx.doi.org/10.1107/s0108767313098723.

Full text

APA, Harvard, Vancouver, ISO, and other styles

16

Chakraborty, Shaunak, Somnath Ganguly, and Gautam R. Desiraju. "Synthon transferability probed with IR spectroscopy: cytosine salts as models for salts of lamivudine." CrystEngComm 16, no. 22 (2014): 4732–41. http://dx.doi.org/10.1039/c3ce42156b.

Full text

Abstract:

Co-crystal screening of the anti-HIV drug lamivudine was carried out with dicarboxylic acids as co-formers. Salts of cytosine, a molecule that incorporates critical structural features of lamivudine, with the same co-formers, were taken as model systems for IR spectroscopic studies of the synthons in the salts of lamivudine.

APA, Harvard, Vancouver, ISO, and other styles

17

Perera, Manomi D., Abhijeet S. Sinha, and Christer B. Aakeröy. "Enhancing chemical stability of tetranitro biimidazole-based energetic materials through co-crystallization." Canadian Journal of Chemistry 98, no. 7 (July 2020): 358–64. http://dx.doi.org/10.1139/cjc-2019-0472.

Full text

Abstract:

Co-crystallization technology was employed as a way of solving two problems hampering the usefulness of 4,4′,5,5′-tetranitro-2,2′biimidazole (TNBI) as a viable energetic material, namely hygroscopicity and corrosiveness (high acidity). Co-crystal screening was carried out with 15 co-formers containing nitrogen or oxygen as the primary hydrogen-bond acceptor site. Formation of co-crystals was confirmed by IR spectroscopy and DSC, and suitable co-crystals were then analysed via single-crystal X-ray diffraction. In each case, the formation of a co-crystal was driven by the formation of multiple N–H···N or N–H···O hydrogen bonds between TNBI and the co-former. The N-oxide based acceptors produce better energetic materials due to a more optimal oxygen balance. Hygroscopicity evaluations and corrosion tests revealed that the unavailability of N–H protons in the co-crystals of TNBI reduce hygroscopicity and suppress the chemical acidity of the free parent compound thereby making it substantially easier to handle, store, and transport.

APA, Harvard, Vancouver, ISO, and other styles

18

Smialek, James, and Simon Gray. "Low Temperature Hot Corrosion Screening of Single Crystal Superalloys." Materials 11, no. 11 (October 25, 2018): 2098. http://dx.doi.org/10.3390/ma11112098.

Full text

Abstract:

Single crystal superalloys were screened in Type II molten (Na,K)-sulfate hot corrosion re-coat tests in air +300 ppm SO2 at 700 °C. They exhibited large 20–40 mg/cm2 weight changes, repeated spallation, and non-protective, 25–50 μm thick corrosion layers after 300 h of testing. Scale cross sections revealed dual outer Ni(Co)O and inner Al(Cr)S-rich corrosion layers. This chemical differentiation was partially consistent with previous models of oxide fluxing, alloy sulfidation, NiO micro-channel diffusion, and synergistic dissolution mechanisms. Broad shallow pits or uniform attack morphologies were consistent with prior studies performed in high >100 ppm pSO2 environments. Higher Mo experimental alloys trended toward more degradation, producing 100 μm thick scales with distinct Al(Cr)S-rich inner layers or 500 μm thick NiO. The aggressive behavior in these environments supports the need for LTHC-resistant coatings for single crystal superalloys.

APA, Harvard, Vancouver, ISO, and other styles

19

Saganowska, Patrycja, and Marek Wesolowski. "DSC as a screening tool for rapid co-crystal detection in binary mixtures of benzodiazepines with co-formers." Journal of Thermal Analysis and Calorimetry 133, no. 1 (December 4, 2017): 785–95. http://dx.doi.org/10.1007/s10973-017-6858-3.

Full text

APA, Harvard, Vancouver, ISO, and other styles

20

Cai, Linhong, Lan Jiang, Cong Li, Xiaoshu Guan, Li Zhang, and Xiangnan Hu. "Multicomponent Crystal of Metformin and Barbital: Design, Crystal Structure Analysis and Characterization." Molecules 26, no. 14 (July 20, 2021): 4377. http://dx.doi.org/10.3390/molecules26144377.

Full text

Abstract:

The formation of most multicomponent crystals relies on the interaction of hydrogen bonds between the components, so rational crystal design based on the expected hydrogen-bonded supramolecular synthons was employed to establish supramolecular compounds with desirable properties. This theory was put into practice for metformin to participate in more therapeutic fields to search for a fast and simple approach for the screening of candidate crystal co-formers. The prediction of intermolecular synthons facilitated the successful synthesis of a new multicomponent crystal of metformin (Met) and barbital (Bar) through an anion exchange reaction and cooling crystallization method. The single crystal X-ray diffraction analysis demonstrated the hydrogen bond-based ureide/ureide and guanidine/ureide synthons were responsible for the self-assembly of the primary structural motif and extended into infinite supramolecular heterocatemeric structures.

APA, Harvard, Vancouver, ISO, and other styles

21

Kawahata, Masatoshi, Masahide Tominaga, Yuki Kawanishi, and Kentaro Yamaguchi. "Co-crystal screening of disubstituted adamantane molecules with N-heterocyclic moieties for hydrogen-bonded arrays." Journal of Molecular Structure 1177 (February 2019): 511–18. http://dx.doi.org/10.1016/j.molstruc.2018.09.093.

Full text

APA, Harvard, Vancouver, ISO, and other styles

22

Morrison, Henry, Melissa Mrozek-Morrison, Josh Toschi, Van Luu, Helming Tan, and Dominick Daurio. "High Throughput Bench-Top Co-crystal Screening via a Floating Foam Rack/Sonic Bath Method." Organic Process Research & Development 17, no. 3 (November 12, 2012): 533–39. http://dx.doi.org/10.1021/op3002382.

Full text

APA, Harvard, Vancouver, ISO, and other styles

23

Budiman, Arif, Sandra Megantara, Putri Raraswati, and Tazyinul Qoriah. "SOLID DOSAGE FORM DEVELOPMENT OF GLIBENCLAMIDE WITH INCREASING THE SOLUBILITY AND DISSOLUTION RATE USING COCRYSTALLIZATION." International Journal of Applied Pharmaceutics 10, no. 6 (November 22, 2018): 181. http://dx.doi.org/10.22159/ijap.2018v10i6.29257.

Full text

Abstract:

Objective: The aim of this study was to develop a solid dosage form of glibenclamide with increasing the solubility properties of glibenclamide with cocrystallization method.Methods: Virtual screening was performed to investigate the interaction between glibenclamide and a co-former. Saccharin, the selected co-former, then co-crystallized with glibenclamide with equimolar ratios of 1:1 and 1:2 using the solvent evaporation method. Further characterization was performed using an infra-red (IR) spectrophotometer, differential scanning calorimetry (DSC), and powder x-ray diffraction (PXRD).Results: Co-crystals of 1:2 equimolar ratio were more highly soluble compared to pure glibenclamide (30-fold for 12 h and 24-fold for 24 h). The dissolution rate had also increased from 46.838% of pure glibenclamide to 77.655% of glibenclamide co-crystal in 60 min. There was no chemical reaction observed during the co-crystallization process based on the IR spectrum. However, there was a new peak in the X-Ray diffractogram and a reduction of melting point in the DSC curve, indicating the formation of co-crystals.Conclusion: The optimal co-crystal ratio of glibenclamide-saccharin was found to be 1:2, which was successful in improving the solubility of glibenclamide.

APA, Harvard, Vancouver, ISO, and other styles

24

Sugimoto, Kunihisa, Shogo Kawaguchi, and Michitaka Takemoto. "Structural characterization of caffeine–oxalic acid co-crystals from the powder diffraction pattern at the SPring-8 BL02B2 beamline." Powder Diffraction 32, S1 (April 10, 2017): S19—S26. http://dx.doi.org/10.1017/s088571561700032x.

Full text

Abstract:

In this work, we developed an X-ray powder diffractometer system equipped with six solid-state detectors and used it to perform ab initio structure determination from the powder diffraction pattern data obtained for a caffeine–oxalic acid co-crystal. The crystal structure obtained from the powder diffraction data was consistent with the previously solved single-crystal structure (Trask reference), although slightly larger (by about 2%). The co-crystallization of pharmaceutically active molecules can modulate their physical properties such as solubility, stability, and bioavailability. For the investigation of pharmaceutical complexes, the ability to visualize molecular interactions such as hydrogen bonding would be very helpful toward understanding their physical properties. Given the rate at which the high-throughput screening of pharmaceutical complexes has grown, an analogous high-volume, high-resolution X-ray powder diffraction technique with high-throughput data collection ability would be useful. We also solved the crystal structures of an inorganic complex and metal organic framework, zinc acetate dihydrate and CPL-1, in order to demonstrate the performance of our new diffractometer system.

APA, Harvard, Vancouver, ISO, and other styles

25

Noonan, Terence J., Kelly Chibale, Susan A. Bourne, and Mino R. Caira. "A preformulation co-crystal screening case study: Polymorphic co-crystals of an imidazopyridazine antimalarial drug lead with the coformer succinic acid." Journal of Molecular Structure 1204 (March 2020): 127561. http://dx.doi.org/10.1016/j.molstruc.2019.127561.

Full text

APA, Harvard, Vancouver, ISO, and other styles

26

Patel, Diksha J., and Prashant K. Puranik. "Pharmaceutical Co-crystal : An Emerging Technique to enhance Physicochemical properties of drugs." International Journal of ChemTech Research 13, no. 3 (2020): 283–90. http://dx.doi.org/10.20902/ijctr.2019.130326.

Full text

Abstract:

Major constraints in development of new product are poor aqueous solubility, stability and low oral bioavailability, low permeability. As majority of drugs marketed worldwide are administered by oral route and about 40% -50% of the new molecular entities were never invade into the market because of such biopharmaceutical issues.So issues related to poor physiochemical property of an active pharmaceutical ingredient (API) can be resolved using cocrystallization approach.Crystallization emerge as potential technique for enhancement of solubility of poorly aqueous soluble drugs also helps to improve physicochemical with preserving the pharmacological properties of the API . Cocrystals are solids that are crystalline single-phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates/hydrates nor simple salts. It is multicomponent system in which one component is API and another is called coformer. Coformer selection is the main challenging step during cocrystal synthesis , so various screening methods for the selection of coformers was explained . This article also summarizes differences between cocrystals with salts, solvates and hydrates along with the implications and limitations of cocrystals .It also provides a brief review on different methods of cocrystal formation and characterization techniuqes of cocrystals. Lastly this article highlights 85 synthetic and 14 herbal cocrystals along with its method of preparation and coformers used.

APA, Harvard, Vancouver, ISO, and other styles

27

Berry, David J., Colin C. Seaton, William Clegg, Ross W. Harrington, Simon J. Coles, Peter N. Horton, Michael B. Hursthouse, et al. "Applying Hot-Stage Microscopy to Co-Crystal Screening: A Study of Nicotinamide with Seven Active Pharmaceutical Ingredients." Crystal Growth & Design 8, no. 5 (May 2008): 1697–712. http://dx.doi.org/10.1021/cg800035w.

Full text

APA, Harvard, Vancouver, ISO, and other styles

28

Manin, Alex N., Ksenia V. Drozd, Artem O. Surov, Andrei V. Churakov, Tatyana V. Volkova, and German L. Perlovich. "Identification of a previously unreported co-crystal form of acetazolamide: a combination of multiple experimental and virtual screening methods." Physical Chemistry Chemical Physics 22, no. 36 (2020): 20867–79. http://dx.doi.org/10.1039/d0cp02700f.

Full text

APA, Harvard, Vancouver, ISO, and other styles

29

Chan, H. C. Stephen, John Kendrick, Marcus A. Neumann, and Frank J. J. Leusen. "Towards ab initio screening of co-crystal formation through lattice energy calculations and crystal structure prediction of nicotinamide, isonicotinamide, picolinamide and paracetamol multi-component crystals." CrystEngComm 15, no. 19 (2013): 3799. http://dx.doi.org/10.1039/c3ce40107c.

Full text

APA, Harvard, Vancouver, ISO, and other styles

30

Patel, Nishadh A. "A Review on Significance of Identifying an Appropriate Solid Form Duringdrug Discovery and Product Development." Material Science Research India 18, no. 2 (August 30, 2021): 154–70. http://dx.doi.org/10.13005/msri/180204.

Full text

Abstract:

In recent years, solid form screening has become an integral and mandatory part of drug development. Solid form screening typically involves producing and characterizingmaximum possible solid forms of a potential drug candidate. Different types of solid forms for future drug product development includes salt screening, co-crystal screening, crystallization process development, polymorph screening as well as amorphous solid dispersion screening.Screening studies of a solid form is a set of carefully designed experiments that requires use of advanced analytical techniques to collect analytical data followed by a thoughtful data analysis.This solid form screening studies guide an important decision-making of lead solid form whichis likely to play a vital role during the pharmaceutical product development lifecycle. The selection criteria include pharmaceutically relevant properties, such as therapeutic efficacy and processing characteristics as well as role of physicochemical properties (i.e. solubility, dissolution rate, hygroscopicity, physical stability and chemical purity) in drug product development. A selected solid form, if thermodynamically unstable, it may undergo solid form changes upon exposure to environmental conditions such as temperature and relative humidity as well as manufacturing stress during the pharmaceutical unit operations. In thepresent work, fundamentals of solid form screening are discussed, including the experimental screening methodologies as well as characterization and analysis of solid forms. The importance of drug product risk assessment pertaining to the desired solid form are also discussed here.

APA, Harvard, Vancouver, ISO, and other styles

31

Coudrat, Thomas, Arthur Christopoulos, Patrick Michael Sexton, and Denise Wootten. "Structural features embedded in G protein-coupled receptor co-crystal structures are key to their success in virtual screening." PLOS ONE 12, no. 4 (April 5, 2017): e0174719. http://dx.doi.org/10.1371/journal.pone.0174719.

Full text

APA, Harvard, Vancouver, ISO, and other styles

32

Lin, Hong-Liang, Gang-Chun Zhang, and Shan-Yang Lin. "Real-time co-crystal screening and formation between indomethacin and saccharin via DSC analytical technique or DSC–FTIR microspectroscopy." Journal of Thermal Analysis and Calorimetry 120, no. 1 (May 10, 2014): 679–87. http://dx.doi.org/10.1007/s10973-014-3787-2.

Full text

APA, Harvard, Vancouver, ISO, and other styles

33

Kumar, Sivakumar Prasanth, and Prakash Chandra Jha. "Multi-Pharmacophore Modeling of Caspase-3 Inhibitors using Crystal, Dock and Flexible Conformation Schemes." Combinatorial Chemistry & High Throughput Screening 21, no. 1 (March 20, 2018): 26–40. http://dx.doi.org/10.2174/1386207321666180102114917.

Full text

Abstract:

Aim and Objective: Numerous caspase-3 drug discovery projects were found to have relied on single receptor as the template to recognize most promising small molecule candidates using docking approach. Alternatively, some researchers were contingent upon ligand-based alignment to build up an empirical relationship between ligand functional groups and caspase-3 inhibitory activity quantitatively. To connect both caspase-3 receptor details and its inhibitors chemical functionalities, this study was undertaken to develop receptor- and ligand-pharmacophore models based on different conformational schemes. Material and Methods: A multi-pharmacophore modeling strategy is carried out based on three conformational schemes of pharmacophore hypothesis generation to screen caspase-3 inhibitors from database. The schemes include (i) flexible (conformations unrestricted or flexible during pharmacophore mapping), (ii) dock (conformations obtained using FlexX docking method) and (iii) crystal (extracted from multiple caspase-3-ligand complexes from PDB repository) conformations of query ligands. The pharmacophore models developed using these conformational schemes were then used to identify probable caspase-3 inhibitors from ZINC database. Results: We noticed better sensitivity with good specificity measures returned by candidate pharmacophore hypotheses across each conformation type and recognized crucial pharmacophore features that enable caspase-3 binding. Pharmacophore modeling based on flexible conformational scheme indicated that the crystal structure 3KJF (AAAADH) is the best receptor structure to perform receptor-based pharmacophore screening of caspase-3 inhibitors. When multiple crystal structures were included, the hypothesis (HAAA) is more generalized. Superimposition of multiple co-crystal ligands from various caspase-3 PDB entries in crystallographic binding mode revealed similar hypothesis (HAAA). Further, FlexX-guided dock conformations of validation dataset showed that the crystal structure 1RE1 is the best-suited for dock-based pharmacophore models. Database screening using these pharmacophore hypotheses identified N'-[6-(benzimidazol-1-yl)-5-nitro-pyrimidin-4-yl]-4 methylbenzenesulfonohydrazide and 2-nitro-N'-[5-nitro-6-[N'-(p-tolylsulfonyl)hydrazino]pyrimidin-4- yl]benzohydrazide as the probable caspase-3 inhibitors. Conclusion: N'-[6-(benzimidazol-1-yl)-5-nitro-pyrimidin-4-yl]-4 methylbenzenesulfonohydrazide and 2-nitro-N'-[5-nitro-6-[N'-(p-tolylsulfonyl)hydrazino]pyrimidin-4-yl]benzohydrazide may be tested for caspase-3 inhibition. We believe that potential caspase-3 inhibitors can be recognized efficiently by adapting multi-pharmacophore models in database screening.

APA, Harvard, Vancouver, ISO, and other styles

34

Yuoh, Amah Colette Benedicta, Moise Ondoh Agwara, Divine Mbom Yufanyi, Mariam Aseng Conde, Rajamony Jagan, and Kenneth Oben Eyong. "Synthesis, Crystal Structure, and Antimicrobial Properties of a Novel 1-D Cobalt Coordination Polymer with Dicyanamide and 2-Aminopyridine." International Journal of Inorganic Chemistry 2015 (June 29, 2015): 1–8. http://dx.doi.org/10.1155/2015/106838.

Full text

Abstract:

A novel one-dimensional coordination polymer bis(2-aminopyridine)-μ-bis(dicyanamido) cobaltate(II) has been synthesized and characterized by elemental analyses and infrared and ultraviolet visible spectroscopies and the structure has been determined by single crystal X-ray diffraction. Co(II) ion in the complex is coordinated to two axial 2-aminopyridine ligands through the pyridine N-atom and four equatorial dicyanamide ligands to give a CoN6 slightly distorted octahedral coordination environment around the metal ion. The amino N-atom forms intrachain hydrogen bonds. Antimicrobial screening of the complex against eight pathogenic microorganisms (four bacteria and four fungi) isolated from humans, indicates that the complex is moderately active.

APA, Harvard, Vancouver, ISO, and other styles

35

Recht, Michael I., Vandana Sridhar, John Badger, Pierre-Yves Bounaud, Cheyenne Logan, Barbara Chie-Leon, Vicki Nienaber, and Francisco E. Torres. "Identification and Optimization of PDE10A Inhibitors Using Fragment-Based Screening by Nanocalorimetry and X-ray Crystallography." Journal of Biomolecular Screening 19, no. 4 (December 27, 2013): 497–507. http://dx.doi.org/10.1177/1087057113516493.

Full text

Abstract:

Fragment-based lead discovery (FBLD) is a technique in which small, low-complexity chemical fragments of 6 to 15 heavy atoms are screened for binding to or inhibiting activity of the target. Hits are then linked and/or elaborated into tightly binding ligands, ideally yielding early lead compounds for drug discovery. Calorimetry provides a label-free method to assay binding and enzymatic activity that is unaffected by the spectroscopic properties of the sample. Conventional microcalorimetry is hampered by requiring large quantities of reagents and long measurement times. Nanocalorimeters can overcome these limitations of conventional isothermal titration calorimetry. Here we use enthalpy arrays, which are arrays of nanocalorimeters, to perform an enzyme activity-based fragment screen for competitive inhibitors of phosphodiesterase 10A (PDE10A). Two dozen fragments with KI <2 mM were identified and moved to crystal soaking trials. All soak experiments yielded high-resolution diffraction, with two-thirds of the fragments yielding high-resolution co-crystal structures with PDE10A. The structural information was used to elaborate fragment hits, yielding leads with KI <1 µM. This study shows how array calorimetry can be used as a prescreening method for fragment-based lead discovery with enzyme targets and paired successfully with an X-ray crystallography secondary screen.

APA, Harvard, Vancouver, ISO, and other styles

36

Korczynska, Magdalena, Daniel Le, Elisabet Gregori-Puigjané, Noah Younger, Tobias Krojer, Anthony Tumber, Udo Oppermann, Danica Galonić Fujimori, and Brian Shoichet. "Virtual Screening of Histone Lysine Demethylase(JMJD2) identifies new inhibitors." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C820. http://dx.doi.org/10.1107/s2053273314091797.

Full text

Abstract:

The JmjC domain-containing proteins are hydroxylases that confer posttranslational modifications on histone tails, by removing methylation marks on methylated lysine residues. This serves to either promote or repress gene transcription. The JMJD2A-D family members include the enzyme Jumonji domain 2C (JMJD2C), which specifically demethylates di- and trimethylated histone H3 at Lys 9 or Lys 36.[1] Dysregulation of JMJD2C has been implicated in prostate, colonic, and breast cancer as the demethylase can modify the expression levels of oncogenes.[2] The goal of the present study was to identify potent and selective small-molecule inhibitors of JMJD2C, to be used as chemical biology tools to further investigate the role of JMJD2C in cell proliferation and survival. Using high-resolution crystal structures of the JMJD2 subfamily members as templates, we have performed a small molecule virtual docking screen. From the ~3 million molecules that were docked, this experiment identified 21 compounds as possible leads. These compounds were tested against JMJD2C in enzymatic assays and here we report an overall hit rate of 76%, with 8 compounds demonstrating an IC50 of 176μM to 1.18μM. A molecule containing a salicylate core was selected as a candidate for optimization and thus far we have completed several rounds of iterative target-specific compound docking, hybrid molecule design, compound synthesis and in vitro characterization. Notably, our method demonstrated a substantial increase in potency when we linked two docked fragments together and further derivatized this new scaffold, through which we have successfully derived a 65nM inhibitor of JMJD2C. A compound representing the inhibitor scaffold has been co-crystallized with JMJD2A to a resolution of 2.4 Å. In the crystal structure each asymmetric unit contains two JMJD2A monomers, each bound to a single inhibitor molecule. This complex-structure superposes well with the docked pose for the hybrid series of compounds. We are now focusing our efforts on identifying an inhibitor that is selective for the JMJD2 family over other JmjC domain-containing proteins.

APA, Harvard, Vancouver, ISO, and other styles

37

Palanisamy, Vasanthi, Palash Sanphui, Muthuramalingam Prakash, and Vladimir Chernyshev. "Multicomponent solid forms of the uric acid reabsorption inhibitor lesinurad and cocrystal polymorphs with urea: DFT simulation and solubility study." Acta Crystallographica Section C Structural Chemistry 75, no. 8 (July 9, 2019): 1102–17. http://dx.doi.org/10.1107/s2053229619008829.

Full text

Abstract:

Lesinurad (systematic name: 2-{[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid, C17H14BrN3O2S) is a selective uric acid reabsorption inhibitor related to gout, which exhibits poor aqueous solubility. High-throughput solid-form screening was performed to screen for new solid forms with improved pharmaceutically relevant properties. During polymorph screening, we obtained two solvates with methanol (CH3OH) and ethanol (C2H5OH). Binary systems with caffeine (systematic name: 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione, C8H10N4O2) and nicotinamide (C6H6N2O), polymorphs with urea (CH4N2O) and eutectics with similar drugs, like allopurinol and febuxostat, were prepared using the crystal engineering approach. All these novel solid forms were confirmed by XRD, DSC and FT–IR. The crystal structures were solved by single-crystal and powder X-ray diffraction. The crystal structures indicate that the lesinurad molecule is highly flexible and the triazole moiety, along with the rotatable thioacetic acid (side chain) and cyclopropane ring, is almost perpendicular to the planar naphthalene moiety. The carboxylic acid–triazole heterosynthon in the drug is interrupted by the presence of methanol and ethanol molecules in their crystal structures and forms intermolecular macrocyclic rings. The caffeine cocrystal maintains the consistency of the acid–triazole heterosynthons as in the drug and, in addition, they are bound by several auxiliary interactions. In the binary system of nicotinamide and urea, the acid–triazole heterosynthon is replaced by an acid–amide synthon. Among the urea cocrystal polymorphs, Form I (P\overline{1}, 1:1) consists of an acid–amide (urea) heterodimer, whereas in Form II (P21/c, 2:2), both acid–amide heterosynthons and urea–urea dimers co-exist. Density functional theory (DFT) calculations further support the experimentally observed synthon hierarchies in the cocrystals. Aqueous solubility experiments of lesinurad and its binary solids in pH 5 acetate buffer medium indicate the apparent solubility order lesinurad–urea Form I (43-fold) > lesinurad–caffeine (20-fold) > lesinurad–allopurinol (12-fold) ≃ lesinurad–nicotinamide (11-fold) > lesinurad, and this order is correlated with the crystal structures.

APA, Harvard, Vancouver, ISO, and other styles

38

Lountos, George T., Xue Zhi Zhao, Evgeny Kiselev, Joseph E. Tropea, Danielle Needle, Yves Pommier, Terrence R. Burke, and David S. Waugh. "Identification of a ligand binding hot spot and structural motifs replicating aspects of tyrosyl-DNA phosphodiesterase I (TDP1) phosphoryl recognition by crystallographic fragment cocktail screening." Nucleic Acids Research 47, no. 19 (June 14, 2019): 10134–50. http://dx.doi.org/10.1093/nar/gkz515.

Full text

Abstract:

Abstract Tyrosyl DNA-phosphodiesterase I (TDP1) repairs type IB topoisomerase (TOP1) cleavage complexes generated by TOP1 inhibitors commonly used as anticancer agents. TDP1 also removes DNA 3′ end blocking lesions generated by chain-terminating nucleosides and alkylating agents, and base oxidation both in the nuclear and mitochondrial genomes. Combination therapy with TDP1 inhibitors is proposed to synergize with topoisomerase targeting drugs to enhance selectivity against cancer cells exhibiting deficiencies in parallel DNA repair pathways. A crystallographic fragment screening campaign against the catalytic domain of TDP1 was conducted to identify new lead compounds. Crystal structures revealed two fragments that bind to the TDP1 active site and exhibit inhibitory activity against TDP1. These fragments occupy a similar position in the TDP1 active site as seen in prior crystal structures of TDP1 with bound vanadate, a transition state mimic. Using structural insights into fragment binding, several fragment derivatives have been prepared and evaluated in biochemical assays. These results demonstrate that fragment-based methods can be a highly feasible approach toward the discovery of small-molecule chemical scaffolds to target TDP1, and for the first time, we provide co-crystal structures of small molecule inhibitors bound to TDP1, which could serve for the rational development of medicinal TDP1 inhibitors.

APA, Harvard, Vancouver, ISO, and other styles

39

Lewis, Hal A., Fred Zhang, Richard Romero, Pierre-Yves Bounaud, Mark E. Wilson, and Andreas Gosberg. "Co-Crystal Structures of 7-Azaindole Inhibitors of Wild-Type and T315I Imatinib-Resistant Mutant Forms of the BCR-ABL Tyrosine Kinase." Blood 110, no. 11 (November 16, 2007): 1018. http://dx.doi.org/10.1182/blood.v110.11.1018.1018.

Full text

Abstract:

Abstract Chronic myelogenous leukemia (CML) arises from uncontrolled cell growth driven by a constitutively active BCR-ABL fusion protein tyrosine kinase, which is the product of the pathognomonic Philadelphia chromosomal translocation. Imatinib mesylate (Gleevec) is a BCR-ABL inhibitor used as a first line treatment of CML. Although imatinib is highly effective in chronic phase CML, in advanced disease patients frequently relapse due to the emergence of drug resistance. Approximately two-thirds of resistance is caused by point mutations in the BCR-ABL kinase domain, which give rise to active mutant forms of the enzyme that are insensitive to Gleevec. The T315I mutation represents one of the most common causes of resistance, is resistant to the second generation BCR-ABL inhibitors dasatinib and nilotinib, and represents an important and challenging target for discovery of next generation targeted CML treatments. We have applied X-ray crystallographic screening of our FAST™ fragment library and structure-guided hit-to-lead optimization to identify potent inhibitors of both wild-type and T315I mutant BCR-ABL. These efforts yielded a 7-azaindole compound series that exhibits binding to and inhibition of both wild-type and T315I BCR-ABL. Methods: Wild-type (with Y393F) and T315I Abl kinase domain protein were expressed in E. coli and purified to homogeneity. These proteins were crystallized in the presence of a reference inhibitor followed by addition of the 7-azaindole series compounds soaked into the preformed crystals to displace the reference compound, giving the desired co-crystal. X-ray diffraction data were recorded at the company’s proprietary synchrotron beamline SGX-CAT at the Advanced Photon Source. Three-dimensional enzyme-inhibitor co-crystal structures were determined by molecular replacement and refined to permit modeling of bound ligand. Results: Both wild-type and T315I Abl structures revealed enzyme in the active conformation with inhibitors bound to the kinase hinge region. The crystal structure of 2-amino-5-[3-(1-ethyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethylbenzamide in complex with T315I, illustrates the typical binding mode which is independent of the 315 residue, and therefore accounts for the compound inhibiting the T315I mutant form of BCR-ABL (see figure). The inhibitor binds to the hinge region of ABL utilizing hydrogen bonding to backbone carbonyl of Glu316 and NH of Met318, with the pyrazole ring stacking in a lipophilic pocket between Phe382 and Tyr253. In addition, the benzamide carbonyl participates in a hydrogen bond interactioin with the backbone-NH of Glu249 of the p-loop. Conclusions: X-ray crystallographic fragment screening and co-crystal structure studies have been successfully employed in discovery/optimization of 7-azaindole series compounds, yielding potent, selective inhibitors of both wild-type and imatinib-resistant forms of BCR-ABL. Figure Figure

APA, Harvard, Vancouver, ISO, and other styles

40

Müller, Ilka. "Guidelines for the successful generation of protein–ligand complex crystals." Acta Crystallographica Section D Structural Biology 73, no. 2 (February 1, 2017): 79–92. http://dx.doi.org/10.1107/s2059798316020271.

Full text

Abstract:

With continuous technical improvements at synchrotron facilities, data-collection rates have increased dramatically. This makes it possible to collect diffraction data for hundreds of protein–ligand complexes within a day, provided that a suitable crystal system is at hand. However, developing a suitable crystal system can prove challenging, exceeding the timescale of data collection by several orders of magnitude. Firstly, a useful crystallization construct of the protein of interest needs to be chosen and its expression and purification optimized, before screening for suitable crystallization and soaking conditions can start. This article reviews recent publications analysing large data sets of crystallization trials, with the aim of identifying factors that do or do not make agoodcrystallization construct, and gives guidance in the design of an expression construct. It provides an overview of common protein-expression systems, addresses how ligand binding can be both help and hindrance for protein purification, and describes ligand co-crystallization and soaking, with an emphasis on troubleshooting.

APA, Harvard, Vancouver, ISO, and other styles

41

Ballone, Alice, Roxanne A. Lau, Fabian P. A. Zweipfenning, and Christian Ottmann. "A new soaking procedure for X-ray crystallographic structural determination of protein–peptide complexes." Acta Crystallographica Section F Structural Biology Communications 76, no. 10 (September 15, 2020): 501–7. http://dx.doi.org/10.1107/s2053230x2001122x.

Full text

Abstract:

Interactions between a protein and a peptide motif of its protein partner are prevalent in nature. Often, a protein also has multiple interaction partners. X-ray protein crystallography is commonly used to examine these interactions in terms of bond distances and angles as well as to describe hotspots within protein complexes. However, the crystallization process presents a significant bottleneck in structure determination since it often requires notably time-consuming screening procedures, which involve testing a broad range of crystallization conditions via a trial-and-error approach. This difficulty is also increased as each protein–peptide complex does not necessarily crystallize under the same conditions. Here, a new co-crystallization/peptide-soaking method is presented which circumvents the need to return to the initial lengthy crystal screening and optimization processes for each consequent new complex. The 14-3-3σ protein, which has multiple interacting partners with specific peptidic motifs, was used as a case study. It was found that co-crystals of 14-3-3σ and a low-affinity peptide from one of its partners, c-Jun, could easily be soaked with another interacting peptide to quickly and easily generate new structures at high resolution. Not only does this significantly reduce the production time, but new 14-3-3–peptide structures that were previously not accessible with the 14-3-3σ isoform, despite screening hundreds of other different conditions, were now also able to be resolved. The findings achieved in this study may be considered as a supporting and practical guide to potentially enable the acceleration of the crystallization process of any protein–peptide system.

APA, Harvard, Vancouver, ISO, and other styles

42

Bohn, Markus-Frederik, and Celia A. Schiffer. "REdiii: a pipeline for automated structure solution." Acta Crystallographica Section D Biological Crystallography 71, no. 5 (April 24, 2015): 1059–67. http://dx.doi.org/10.1107/s139900471500303x.

Full text

Abstract:

High-throughput crystallographic approaches require integrated software solutions to minimize the need for manual effort.REdiiiis a system that allows fully automated crystallographic structure solution by integrating existing crystallographic software into an adaptive and partly autonomous workflow engine. The program can be initiated after collecting the first frame of diffraction data and is able to perform processing, molecular-replacement phasing, chain tracing, ligand fitting and refinement without further user intervention. Preset values for each software component allow efficient progress with high-quality data and known parameters. The adaptive workflow engine can determine whether some parameters require modifications and choose alternative software strategies in case the preconfigured solution is inadequate. This integrated pipeline is targeted at providing a comprehensive and efficient approach to screening for ligand-bound co-crystal structures while minimizing repetitiveness and allowing a high-throughput scientific discovery process.

APA, Harvard, Vancouver, ISO, and other styles

43

Setiawati, Agustina, Florentinus Dika Octa Riswanto, Sri Hartati Yuliani, and Enade Perdana Istyastono. "Retrospective Validation of a Structure-Based Virtual Screening Protocol to Identify Ligands for Estrogen Receptor Alpha and Its Application to Identify the Alpha-Mangostin Binding Pose." Indonesian Journal of Chemistry 14, no. 2 (July 25, 2014): 103–8. http://dx.doi.org/10.22146/ijc.21245.

Full text

Abstract:

The publicly available enhanced data of ligands and decoys for estrogen receptor alpha (ERα) which were recently published has made the retrospective validation of a structure-based virtual screening (SBVS) protocol to identify ligands for ERα possible. In this article, we present the retrospective validation of an SBVS protocol using PLANTS molecular docking software version 1.2 (PLANTS1.2) as the backbone software. The protocol shows better enrichment factor at 1% false positives (EF1%) value and the Area Under Curve (AUC) value of the Receiver Operator Characteristic (ROC) compared to the original published protocol. Moreover, in all 1000 iterative attempts the protocol could reproduce the co-crystal pose of 4-hydroxitamoxifen in ERα binding pocket. It shows that the protocol is not only able to identify potent ligands for ERα but also able to be employed in examining binding pose of known ligand. Thence, the protocol was successfully employed to examine the binding poses of α-mangostin, an ERα ligand found in the Garcinia mangostana, L. pericarp.

APA, Harvard, Vancouver, ISO, and other styles

44

Wahrmund, Rebecca D., Kristiana A. Avad, Stephanie M. Reeve, Jesse A. Jones, Thao La, Richard E. Lee, and Kirk E. Hevener. "1233. Identification of Novel Inhibitors of Clostridioides difficile Enoyl-Reductase II (FabK) by High-Throughput Virtual and Experimental Screening." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S636. http://dx.doi.org/10.1093/ofid/ofaa439.1418.

Full text

Abstract:

Abstract Background Clostridioides difficile is one of only three bacteria categorized as an ‘urgent’ drug-resistant threat by the CDC. This pathogen is responsible for nearly 500,000 hospital-acquired infections and 29,000 deaths per year at a cost of nearly $4.8 billion. There is a critical need for the identification of novel, anti-difficile agents with narrow-spectrum activity that can spare the human microbiome. We previously reported the essentiality of the FAS-II enzyme, enoyl-ACP reductase (FabK) in C. difficile, and the narrow-spectrum activity of a series of phenylimidazole inhibitors. We present here experimental and virtual compound screening studies that identified novel FabK inhibitors with sub-micromolar activity and follow-up SAR and structural studies. Methods Using a novel luminescence assay, 20K diverse compounds from the St. Jude drug-like and lead-like libraries were screened. In parallel, a ligand-based virtual screen was performed against 2.4 million lead- and drug-like compounds from commercial libraries. Hit compounds were confirmed using an orthogonal fluorescence-intensity assay and SAR studies were performed by testing commercially available hit analogs. The most potent inhibitor was advanced into co-crystallography structural studies. Results The compound screening campaigns resulted in the identification of several confirmed hit compounds with low to sub-micromolar activity and novel scaffolds relative to the known phenylimidazole inhibitors. Importantly, the first confirmed nanomolar inhibitor of C. difficile FabK was identified and validated with an IC50 of 0.35 μM. SAR studies of the hits along with a high-resolution co-crystal structure have allowed new insights into the key binding determinants and structural requirements for activity as well as the structural requirements for species specificity. Conclusion The C. difficile FabK enzyme offers a promising narrow-spectrum drug target that can potentially spare the human microbiome. The known activity of the phenylimidazole inhibitor series supports the druggability of this target. The newly discovered inhibitor class presented here further demonstrates the potential of FabK inhibition and will facilitate the development of clinically relevant, narrow-spectrum anti-difficile agents. Disclosures All Authors: No reported disclosures

APA, Harvard, Vancouver, ISO, and other styles

45

Braccini, Simona, Giorgia Rizzi, Lorenzo Biancalana, Alessandro Pratesi, Stefano Zacchini, Guido Pampaloni, Federica Chiellini, and Fabio Marchetti. "Anticancer Diiron Vinyliminium Complexes: A Structure–Activity Relationship Study." Pharmaceutics 13, no. 8 (July 27, 2021): 1158. http://dx.doi.org/10.3390/pharmaceutics13081158.

Full text

Abstract:

A series of 16 novel diiron complexes of general formula [Fe2Cp2(CO)(μ-CO){μ-η1:η3-C(R′)C(R″)CN(R)(Y)}]CF3SO3 (2–7), bearing different substituents on the bridging vinyliminium ligand, was synthesized in 69–95% yields from the reactions of diiron μ-aminocarbyne precursors with various alkynes. The products were characterized by elemental analysis, IR, 1H and 13C NMR spectroscopy; moreover the X-ray structures of 2c (R = Y = CH2Ph, R′ = R″ = Me) and 3a (R = CH2CH=CH2, Y = R′ = Me, R″ = H) were ascertained by single-crystal X-ray diffraction studies. NMR and UV–Vis methods were used to assess the D2O solubility, the stability in aqueous solution at 37 °C and the octanol–water partition coefficients of the complexes. A screening study evidenced a potent cytotoxicity of 2–7 against the A2780 cancer cell line, with a remarkable selectivity compared to the nontumoral Balb/3T3 cell line; complex 4c (R = Cy, Y = R′ = R″ = Me) revealed as the most performant of the series. The antiproliferative activity of a selection of complexes was also assessed on the cisplatin-resistant A2780cisR cancer cell line, and these complexes were capable of inducing a significant ROS production. Moreover, ESI-MS experiments indicated the absence of interaction of selected complexes with cytochrome c and the potentiality to inhibit the thioredoxin reductase enzyme (TrxR).

APA, Harvard, Vancouver, ISO, and other styles

46

Idemudia, Omoruyi G., Alexander P. Sadimenko, Anthony J. Afolayan, and Eric C. Hosten. "Synthesis and Characterization of Bioactive Acylpyrazolone Sulfanilamides and Their Transition Metal Complexes: Single Crystal Structure of 4-Benzoyl-3-methyl-1-phenyl-2-pyrazolin-5-one Sulfanilamide." Bioinorganic Chemistry and Applications 2015 (2015): 1–14. http://dx.doi.org/10.1155/2015/717089.

Full text

Abstract:

Two Schiff base ligands Ampp-Sn1and Bmpp-Sn2, afforded by a condensation reaction between sulfanilamide and the respective acylpyrazolone carbonyl precursors, their Mn(II), Co(II), Ni(II), and Cu(II) complexes prepared by the reaction of ligands and corresponding metal salts in aqueous solutions, were synthesized and then characterized by both analytical and spectroscopic methods, in a view to developing new improved bioactive materials with novel properties. On the basis of elemental analysis, spectroscopic and TGA results, transition metal complexes, with octahedral geometry having two molecules of the bidentate keto-imine ligand each, have been proposed. The single crystal structure of Bmpp-Sn according to X-ray crystallography showed a keto-imine tautomer type of Schiff base, having three intramolecular bonds, one short N2⋯H2⋯O3 hydrogen bond of 1.90 Å and two long C13⋯H13⋯O2 and C32⋯H32⋯O3 hydrogen bonds of 2.48 Å. A moderate to low biological activities have been exhibited by synthesized compounds when compared with standard antimicrobial agents on screening the synthesized compounds againstStaphylococcus aureus,Bacillus pumilus,Proteus vulgaris, andAeromonas hydrophilafor antibacterial activity and against free radical 1, 1-diphenyl-2-picryl-hydrazyl (DPPH) for antioxidant activity.

APA, Harvard, Vancouver, ISO, and other styles

47

Fudulu, Alina, Rodica Olar, Cătălin Maxim, Gina Vasile Scăeţeanu, Coralia Bleotu, Lilia Matei, Mariana Carmen Chifiriuc, and Mihaela Badea. "New Cobalt (II) Complexes with Imidazole Derivatives: Antimicrobial Efficiency against Planktonic and Adherent Microbes and In Vitro Cytotoxicity Features." Molecules 26, no. 1 (December 24, 2020): 55. http://dx.doi.org/10.3390/molecules26010055.

Full text

Abstract:

Three novel Co(II) complexes of the type [Co(C4H5O2)2L2] (where C4H5O2 is methacrylate anion; L = C3H4N2 (imidazole; HIm) (1), C4H6N2 (2-methylimidazole; 2-MeIm) (2), C5H8N2 (2-ethylimidazole; 2-EtIm) (3)) have been synthesized and characterized by elemental analysis, IR and UV-Vis spectroscopic techniques, thermal analysis and single crystal X-ray diffraction. X-ray crystallography revealed for complexes (1) and (2) distorted trigonal bipyramid stereochemistry for Co(II), meanwhile for complex (3) evidenced that the unit cell comprises three molecular units with interesting structural features. In each unit, both stereochemistry adopted by metallic ion and coordination modes of carboxylate anions are different. The screening of antimicrobial activity revealed that Candida albicans planktonic cells were the most susceptible, with minimal inhibitory concentration (MIC) values of 7.8 μg/mL for complexes (1) and (2) and 15.6 μg/mL for complex (3). Complexes (1) and (2) proved to be more active than complex (3) against the tested bacterial strains, both in planktonic and biofilm growth state, with MIC and minimal biofilm eradication concentration (MBEC) values ranging from 15.6 to 62.5 μg/mL, the best antibacterial effects being noticed against Staphylococcus aureus and Pseudomonas aeruginosa. Remarkably, the MBEC values obtained for the four tested bacterial strains were either identical or even lower than the MIC ones. The cytotoxicity assay indicated that the tested complexes affected the cellular cycle of HeLa, HCT-8, and MG63 cells, probably by inhibiting the expression of vimentin and transient receptor potential canonical 1 (TRPC1). The obtained biological results recommend these complexes as potential candidates for the development of novel anti-biofilm agents.

APA, Harvard, Vancouver, ISO, and other styles

48

Pang, Luping, Stephen D. Weeks, Martin Juhás, Sergei V. Strelkov, Jan Zitko, and Arthur Van Aerschot. "Towards Novel 3-Aminopyrazinamide-Based Prolyl-tRNA Synthetase Inhibitors: In Silico Modelling, Thermal Shift Assay and Structural Studies." International Journal of Molecular Sciences 22, no. 15 (July 21, 2021): 7793. http://dx.doi.org/10.3390/ijms22157793.

Full text

Abstract:

Human cytosolic prolyl-tRNA synthetase (HcProRS) catalyses the formation of the prolyl-tRNAPro, playing an important role in protein synthesis. Inhibition of HcProRS activity has been shown to have potential benefits in the treatment of fibrosis, autoimmune diseases and cancer. Recently, potent pyrazinamide-based inhibitors were identified by a high-throughput screening (HTS) method, but no further elaboration was reported. The pyrazinamide core is a bioactive fragment found in numerous clinically validated drugs and has been subjected to various modifications. Therefore, we applied a virtual screening protocol to our in-house library of pyrazinamide-containing small molecules, searching for potential novel HcProRS inhibitors. We identified a series of 3-benzylaminopyrazine-2-carboxamide derivatives as positive hits. Five of them were confirmed by a thermal shift assay (TSA) with the best compounds 3b and 3c showing EC50 values of 3.77 and 7.34 µM, respectively, in the presence of 1 mM of proline (Pro) and 3.45 µM enzyme concentration. Co-crystal structures of HcProRS in complex with these compounds and Pro confirmed the initial docking studies and show how the Pro facilitates binding of the ligands that compete with ATP substrate. Modelling 3b into other human class II aminoacyl-tRNA synthetases (aaRSs) indicated that the subtle differences in the ATP binding site of these enzymes likely contribute to its potential selective binding of HcProRS. Taken together, this study successfully identified novel HcProRS binders from our anti-tuberculosis in-house compound library, displaying opportunities for repurposing old drug candidates for new applications such as therapeutics in HcProRS-related diseases.

APA, Harvard, Vancouver, ISO, and other styles

49

Arnold, Eddy. "Triumphs of Crystallography in Tackling HIV/AIDS: Drugs by Design." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C7. http://dx.doi.org/10.1107/s2053273314099926.

Full text

Abstract:

Crystallography has made extraordinary contributions to our understanding of the biology and chemistry of HIV. Judicious applications of structure-based drug design against HIV-1 protease and reverse transcriptase (RT) has led to the discovery of key drugs that are used in combinations to treat HIV infection. Extensive research and development efforts by pharma, academia, and government have made it possible for an HIV-infected person to live a nearly normal life. I will summarize the elegant structures that have been determined of components of HIV, with an emphasis on the enzyme RT, which my laboratory has studied since 1987. HIV-1 RT is responsible for converting the viral 10-kilobase single-stranded RNA genome to double-stranded DNA. This fascinating and essential enzyme is the target of 13 approved anti-AIDS drugs: 8 nucleoside analog RT inhibitors (NRTIs) and 5 non-nucleoside RT inhibitors (NNRTIs). We have determined crystal structures of wild-type and drug-resistant RTs in complexes with nucleic acid and/or inhibitors. We participated in structure-guided discovery and development of two anti-AIDS drugs with exceptional potency against drug-resistant variants. Crystal structures combined with biochemical data help to elucidate intriguing molecular mechanisms by which HIV-1 develops resistance to different anti-AIDS drugs. Recent crystallographic fragment screening has revealed new allosteric inhibitory binding pockets for future drug discovery. I am very grateful to my many co-workers, colleagues, and friends for their contributions, synchrotron resources at CHESS, BNLS, and APS, and generous funding from NIH in support of research on HIV-1 RT.

APA, Harvard, Vancouver, ISO, and other styles

50

Shamshad, Hina, Abdul Hafiz, Ismail I. Althagafi, Maria Saeed, and Agha Zeeshan Mirza. "Characterization of the Trypanosoma brucei Pteridine Reductase Active- Site using Computational Docking and Virtual Screening Techniques." Current Computer-Aided Drug Design 16, no. 5 (November 9, 2020): 583–98. http://dx.doi.org/10.2174/1573409915666190827163327.

Full text

Abstract:

Background: Human African trypanosomiasis is a fatal disease prevalent in approximately 36 sub-Saharan countries. Emerging reports of drug resistance in Trypanosoma brucei are a serious cause of concern as only limited drugs are available for the treatment of the disease. Pteridine reductase is an enzyme of Trypanosoma brucei. Methods: It plays a critical role in the pterin metabolic pathway that is absolutely essential for its survival in the human host. The success of finding a potent inhibitor in structure-based drug design lies within the ability of computational tools to efficiently and accurately dock a ligand into the binding cavity of the target protein. Here we report the computational characterization of Trypanosoma brucei pteridine reductase (Tb-PR) active-site using twenty-four high-resolution co-crystal structures with various drugs. Structurally, the Tb-PR active site can be grouped in two clusters; one with high Root Mean Square Deviation (RMSD) of atomic positions and another with low RMSD of atomic positions. These clusters provide fresh insight for rational drug design against Tb-PR. Henceforth, the effect of several factors on docking accuracy, including ligand and protein flexibility were analyzed using Fred. Results: The online server was used to analyze the side chain flexibility and four proteins were selected on the basis of results. The proteins were subjected to small-scale virtual screening using 85 compounds, and statistics were calculated using Bedroc and roc curves. The enrichment factor was also calculated for the proteins and scoring functions. The best scoring function was used to understand the ligand protein interactions with top common compounds of four proteins. In addition, we made a 3D structural comparison between the active site of Tb-PR and Leishmania major pteridine reductase (Lm- PR). We described key structural differences between Tb-PR and Lm-PR that can be exploited for rational drug design against these two human parasites. Conclusion: The results indicated that relying just on re-docking and cross-docking experiments for virtual screening of libraries isn’t enough and results might be misleading. Hence it has been suggested that small scale virtual screening should be performed prior to large scale screening.

APA, Harvard, Vancouver, ISO, and other styles

Journal articles on the topic 'Co-crystal screening'

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles