Discovery of new and potent InhA inhibitors as anti-tuberculosis agents: structure based virtual screening validated by biological assays and x-ray crystallography

DOI: 10.1021/acs.jcim.9b00918

Authors: Pharit Kamsri (Nakhon Phanom University) , Chayanin Hanwarinroj (Ubon Ratchathani University) , Naruedon Phusi (Ubon Ratchathani University) , Thimpika Pornprom (Ubon Ratchathani University) , Kampanart Chayajarus (Ubon Ratchathani University) , Auradee Punkvang (Nakhon Phanom University) , Nitima Suttipanta (Ubon Ratchathani University) , Potjanee Srimanote (Thammasat University) , Khomson Suttisintong (National Science and Technology Development Agency, Thailand) , Chomphunuch Songsiriritthigul (Synchrotron Light Research Institute) , Patchreenart Saparpakorn (Kasetsart University) , Supa Hannongbua (Kasetsart University) , Siriluk Rattanabunyong (Kasetsart University) , Supaporn Seetaha (Kasetsart University) , Kiattawee Choowongkomon (Kasetsart University) , Sanya Sureram (Chulabhorn Research Institute) , Prasat Kittakoop (Chulabhorn Research Institute; CHE, Ministry of Education) , Poonpilas Hongmanee (Mahidol University) , Pitak Santanirand (Mahidol University) , Zhaoqiang Chen (Shanghai Institute of Materia Medica) , Weiliang Zhu (Shanghai Institute of Materia Medica) , Rosemary A Blood (University of Bristol) , Yuiko Takebayashi (University of Bristol) , Philip Hinchliffe (University of Bristol) , Adrian J. Mulholland (University of Bristol) , James Spencer (University of Bristol) , Pornpan Pungpo (Ubon Ratchathani University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Chemical Information And Modeling

State: Published (Approved)
Published: December 2019
Diamond Proposal Number(s): 17212

Abstract: The enoyl-acyl carrier protein reductase InhA of M. tuberculosis is an attractive, validated target for anti-tuberculosis 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 anti-tuberculosis 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.

Journal Keywords: Tuberculosis; InhA; Virtual screening; Biological assays; X-ray crystallography

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography