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