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Title: Discovery of New and Potent InhA Inhibitors as Antituberculosis Agents: Structure-Based Virtual Screening Validated by Biological Assays and X-ray Crystallography
Authors: Pharit Kamsri
Chayanin Hanwarinroj
Naruedon Phusi
Thimpika Pornprom
Kampanart Chayajarus
Auradee Punkvang
Nitima Suttipanta
Potjanee Srimanote
Khomson Suttisintong
Chomphunuch Songsiriritthigul
Patchreenart Saparpakorn
Supa Hannongbua
Siriluk Rattanabunyong
Supaporn Seetaha
Kiattawee Choowongkomon
Sanya Sureram
Prasat Kittakoop
Poonpilas Hongmanee
Pitak Santanirand
Zhaoqiang Chen
Weiliang Zhu
Rosemary A. Blood
Yuiko Takebayashi
Philip Hinchliffe
Adrian J. Mulholland
James Spencer
Pornpan Pungpo
South Carolina Commission on Higher Education
Ubon Rajathanee University
Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Chulabhorn Research Institute
Kasetsart University
University of Bristol
Thailand National Nanotechnology Center
Faculty of Medicine, Ramathibodi Hospital, Mahidol University
Thammasat University
Chulabhorn Royal Academy
Synchrotron Light Research Institute (Public Organization)
Nakhon Phanom University
Faculty of Science
Keywords: Chemical Engineering;Chemistry;Computer Science;Social Sciences
Issue Date: 1-Jan-2020
Citation: Journal of Chemical Information and Modeling. (2020)
Abstract: Copyright © 2019 American Chemical Society. 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.
ISSN: 15205142
Appears in Collections:Scopus 2020

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