4 results on '"Supaporn Seetaha"'
Search Results
2. Discovery of New and Potent InhA Inhibitors as Antituberculosis Agents: Structure-Based Virtual Screening Validated by Biological Assays and X-ray Crystallography
- Author
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Pitak Santanirand, Nitima Suttipanta, Siriluk Rattanabunyong, Poonpilas Hongmanee, Patchreenart Saparpakorn, Pornpan Pungpo, Thimpika Pornprom, Adrian J. Mulholland, Supaporn Seetaha, Khomson Suttisintong, Potjanee Srimanote, Kampanart Chayajarus, Rosemary A. Blood, Naruedon Phusi, Zhaoqiang Chen, Sanya Sureram, Pharit Kamsri, Supa Hannongbua, Philip Hinchliffe, Prasat Kittakoop, Kiattawee Choowongkomon, James Spencer, Yuiko Takebayashi, Chomphunuch Songsiriritthigul, Chayanin Hanwarinroj, Weiliang Zhu, and Auradee Punkvang
- Subjects
Stereochemistry ,General Chemical Engineering ,Antitubercular Agents ,Microbial Sensitivity Tests ,Library and Information Sciences ,Crystallography, X-Ray ,01 natural sciences ,Molecular Docking Simulation ,Mycobacterium tuberculosis ,Structure-Activity Relationship ,Bacterial Proteins ,Drug Discovery ,0103 physical sciences ,Structure–activity relationship ,Binding site ,Virtual screening ,Binding Sites ,Molecular Structure ,010304 chemical physics ,biology ,Drug discovery ,Chemistry ,INHA ,Reproducibility of Results ,General Chemistry ,biology.organism_classification ,0104 chemical sciences ,Computer Science Applications ,010404 medicinal & biomolecular chemistry ,Docking (molecular) ,Oxidoreductases - Abstract
The enoyl-acyl carrier protein reductase InhA of Mycobacterium tuberculosis is an attractive, validated target for antituberculosis drug development. Moreover, direct inhibitors of InhA remain effective against InhA variants with mutations associated with isoniazid resistance, offering the potential for activity against MDR isolates. Here, structure-based virtual screening supported by biological assays was applied to identify novel InhA inhibitors as potential antituberculosis agents. High-speed Glide SP docking was initially performed against two conformations of InhA differing in the orientation of the active site Tyr158. The resulting hits were filtered for drug-likeness based on Lipinski’s rule and avoidance of PAINS-like properties and finally subjected to Glide XP docking to improve accuracy. Sixteen compounds were identified and selected for in vitro biological assays, of which two (compounds 1 and 7) showed MIC of 12.5 and 25 μg/mL against M. tuberculosis H37Rv, respectively. Inhibition assays against purified recombinant InhA determined IC50 values for these compounds of 0.38 and 0.22 μM, respectively. A crystal structure of the most potent compound, compound 7, bound to InhA revealed the inhibitor to occupy a hydrophobic pocket implicated in binding the aliphatic portions of InhA substrates but distant from the NADH cofactor, i.e., in a site distinct from those occupied by the great majority of known InhA inhibitors. This compound provides an attractive starting template for ligand optimization aimed at discovery of new and effective compounds against M. tuberculosis that act by targeting InhA.
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- 2019
- Full Text
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3. Computational screening of chalcones acting against topoisomerase IIα and their cytotoxicity towards cancer cell lines
- Author
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Warinthon Chavasiri, Nawee Kungwan, Monika Mueller, Nitchakan Darai, Ritbey Ruga, Kanyani Sangpheak, Thanyada Rungrotmongkol, Peter Wolschann, Chompoonut Rungnim, Chonticha Suwattanasophon, Kiattawee Choowongkomon, and Supaporn Seetaha
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Models, Molecular ,Chalcone ,Topoisomerase iiα ,Cell Survival ,ATPase assay ,Antineoplastic Agents ,Cleavage (embryo) ,01 natural sciences ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Enzyme activator ,Chalcones ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Humans ,Structure–activity relationship ,Cytotoxicity ,Pharmacology ,integumentary system ,biology ,010405 organic chemistry ,Topoisomerase ,lcsh:RM1-950 ,General Medicine ,molecular docking ,0104 chemical sciences ,Enzyme Activation ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,DNA Topoisomerases, Type II ,lcsh:Therapeutics. Pharmacology ,molecular dynamics simulation ,chemistry ,Drug Design ,biology.protein ,Cancer research ,Electrophoresis, Polyacrylamide Gel ,Drug Screening Assays, Antitumor ,DNA ,human topoisomerase IIα ,HeLa Cells ,Research Paper - Abstract
Targeted cancer therapy has become one of the high potential cancer treatments. Human topoisomerase II (hTopoII), which catalyzes the cleavage and rejoining of double-stranded DNA, is an important molecular target for the development of novel cancer therapeutics. In order to diversify the pharmacological activity of chalcones and to extend the scaffold of topoisomerase inhibitors, a series of chalcones was screened against hTopoIIα by computational techniques, and subsequently tested for their in vitro cytotoxicity. From the experimental IC50 values, chalcone 3d showed a high cytotoxicity with IC50 values of 10.8, 3.2 and 21.1 µM against the HT-1376, HeLa and MCF-7 cancer-derived cell lines, respectively, and also exhibited an inhibitory activity against hTopoIIα-ATPase that was better than the known inhibitor, salvicine. The observed ligand–protein interactions from a molecular dynamics study affirmed that 3d strongly interacts with the ATP-binding pocket residues. Altogether, the newly synthesised chalcone 3d has a high potential to serve as a lead compound for topoisomerase inhibitors.
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- 2018
- Full Text
- View/download PDF
4. Application of Site-Specific Spin Labeling for NMR Detecting Inhibitor-Induced Conformational Change of HIV-1 Reverse Transcriptase
- Author
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Takumi Yamaguchi, Supaporn Seetaha, Koichi Kato, Kentaro Ishii, Maho Yagi-Utsumi, Supa Hannongbua, and Kiattawee Choowongkomon
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0301 basic medicine ,Models, Molecular ,Conformational change ,Protein Conformation ,Allosteric regulation ,HIV Infections ,Nuclear Overhauser effect ,010402 general chemistry ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,Drug Discovery ,Humans ,Carbon Radioisotopes ,General Pharmacology, Toxicology and Pharmaceutics ,Nuclear Magnetic Resonance, Biomolecular ,Pharmacology ,Drug discovery ,Chemistry ,Organic Chemistry ,Nuclear magnetic resonance spectroscopy ,Site-directed spin labeling ,Molecular biology ,Reverse transcriptase ,HIV Reverse Transcriptase ,0104 chemical sciences ,030104 developmental biology ,Biophysics ,HIV-1 ,Molecular Medicine ,Reverse Transcriptase Inhibitors ,Target protein - Abstract
Paramagnetism-assisted nuclear magnetic resonance (NMR) techniques can provide long-range structural information complemented with local information derived from chemical-shift perturbation and nuclear Overhauser effect data. Here, we address the application of paramagnetic relaxation enhancement (PRE) to detect inhibitor-induced conformational change of a drug target protein using human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) as a model protein. Using a site-specific spin-labeled HIV-1 RT mutant with selective (13) C labeling, conformation-dependent PREs were successfully observed reflecting the stabilization of an open conformation of this enzyme caused by inhibitor binding. This study demonstrates that the paramagnetism-assisted NMR approach offers an alternative strategy in protein-based drug screening to identify allosteric inhibitors of a target protein.
- Published
- 2015
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