Discovery of New and Potent InhA Inhibitors as Antituberculosis Agents: Structure-Based Virtual Screening Validated by Biological Assays and X-ray Crystallography

doi:10.1021/acs.jcim.9b00918

	Discovery of New and Potent InhA Inhibitors as Antituberculosis Agents: Structure-Based Virtual Screening Validated by Biological Assays and X-ray Crystallography
	Kamsri, Pharit 2; Hanwarinroj, Chayanin 3; Phusi, Naruedon 3; Pornprom, Thimpika 3; Chayajarus, Kampanart 3; Punkvang, Auradee 2; Suttipanta, Nitima 4; Srimanote, Potjanee 5; Suttisintong, Khomson 6; Songsiriritthigul, Chomphunuch 7
刊名	JOURNAL OF CHEMICAL INFORMATION AND MODELING
	2020
卷号	60 期号:1 页码:226-234
ISSN号	1549-9596
DOI	10.1021/acs.jcim.9b00918
通讯作者	Pungpo, Pornpan(pornpan_ubu@yahoo.com)
英文摘要	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 mu g/mL against M. tuberculosis H37Rv, respectively. Inhibition assays against purified recombinant InhA determined IC50 values for these compounds of 0.38 and 0.22 mu M, 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.
资助项目	Thailand Research Fund[RSA5980057] ; RGJ Advanced Programme[RAP60K0009] ; Thailand Graduate Institute of Science and Technology (TGIST)[SCA-CO-2560-4375TH] ; Young Scientist and Technologist Programme (YSTP)[SCA-CO-2561-7260-TH] ; Center of Excellence for Innovation in Chemistry (PERCH-CIC) ; Royal Golden Jubilee Ph.D. Program[PHD/0004/2554] ; BristolBridge antimicrobial resistance network[EPSRC EP/M027546/1] ; CCP-BioSim[EP/M022609/1] ; Ubon Ratchathani University ; NECTEC ; University of Bristol
WOS关键词	CARRIER PROTEIN REDUCTASE ; ENOYL-ACP REDUCTASE ; MYCOBACTERIUM-TUBERCULOSIS ; TARGETING INHA ; CRYSTAL-STRUCTURE ; ACCURATE DOCKING ; GLIDE ; RESISTANCE ; LIGANDS ; COMPLEX
WOS研究方向	Pharmacology & Pharmacy ; Chemistry ; Computer Science
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000510104100022
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281668]
专题	中国科学院上海药物研究所
通讯作者	Pungpo, Pornpan
作者单位	1.Kasetsart Univ, Fac Sci, Dept Chem, Bangkok 10900, Thailand 2.Nakhon Phanom Univ, Div Chem, Fac Sci, Nakhon Phanom 48000, Thailand 3.Ubon Ratchathani Univ, Fac Sci, Dept Chem, Warinchamrap 34190, Ubonratchathani, Thailand 4.Ubon Ratchathani Univ, Fac Pharmaceut Sci, Warinchamrap 34190, Ubonratchathani, Thailand 5.Thammasat Univ, Fac Allied Hlth Sci, Rangsit Campus, Pathum Thani 12120, Thailand 6.Natl Sci & Technol Dev Agcy, Natl Nanotechnol Ctr, Thailand Sci Pk, Pathum Thani 12120, Thailand 7.Synchrotron Light Res Inst Publ Org, Nakhon 30000, Ratchasima, Thailand 8.Kasetsart Univ, Fac Sci, Dept Biochem, Bangkok 10900, Thailand 9.Chulabhorn Res Inst, Bangkok 10210, Thailand 10.Chulabhorn Royal Acad, Chem Biol Program, Chulabhorn Grad Inst, Bangkok 10210, Thailand
推荐引用方式 GB/T 7714	Kamsri, Pharit,Hanwarinroj, Chayanin,Phusi, Naruedon,et al. Discovery of New and Potent InhA Inhibitors as Antituberculosis Agents: Structure-Based Virtual Screening Validated by Biological Assays and X-ray Crystallography[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2020,60(1):226-234.
APA	Kamsri, Pharit.,Hanwarinroj, Chayanin.,Phusi, Naruedon.,Pornprom, Thimpika.,Chayajarus, Kampanart.,...&Pungpo, Pornpan.(2020).Discovery of New and Potent InhA Inhibitors as Antituberculosis Agents: Structure-Based Virtual Screening Validated by Biological Assays and X-ray Crystallography.JOURNAL OF CHEMICAL INFORMATION AND MODELING,60(1),226-234.
MLA	Kamsri, Pharit,et al."Discovery of New and Potent InhA Inhibitors as Antituberculosis Agents: Structure-Based Virtual Screening Validated by Biological Assays and X-ray Crystallography".JOURNAL OF CHEMICAL INFORMATION AND MODELING 60.1(2020):226-234.