title: Discovery of InhA inhibitors with anti-mycobacterial activity through a matched molecular pair approach.
abstract: The Mycobacterium tuberculosis (M. tuberculosis) enoyl-acyl carrier protein reductase (mtInhA) is an attractive enzyme and a thoroughly studied target for tuberculosis therapy. In this study, to identify novel structure-activity relationships (SARs) of mtInhA inhibitors, a series of diphenyl ether derivatives were designed based on the matched molecular pair (MMP) method, and the binding energies of these compounds were subsequently estimated by in silico structure-based drug screening (SBDS) to provide more useful data. Consequently, the 10 unique candidate compounds (KEM1-KEM10) were identified and assessed for the inhibition of mtInhA enzymatic activity, in vitro antibiotic effects against model mycobacteria and toxicity level on both intestinal bacteria and mammalian cells. Among the compounds tested, phenyl group (KEM4) and 2-fluorobenzyl group (KEM7) substitutions produced preferable inhibitory effects on mtInhA enzymatic activity relative to those provided by a furyl group (KES4: base compound) at the terminal of the compound, and KEM7 inhibited the growth of the mycobacteria strain with a lower IC50 value. Moreover, most of the candidate compounds exhibited neither inhibition of the growth of enterobacteria nor toxic effects on mammalian cells, though KEM10 exhibited toxicity against cultured MDCK cells. The structural and experimental information concerning these mtInhA inhibitors identified through MMP-based in silico screening will likely contribute to the lead optimisation of novel antibiotics for M. tuberculosis.
authors.affiliation: Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, 680-4 Kawazu, Iizuka-shi, Fukuoka 820-8502, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Kanetaka
authors.affiliation: Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, 680-4 Kawazu, Iizuka-shi, Fukuoka 820-8502, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Koseki
authors.affiliation: Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, 680-4 Kawazu, Iizuka-shi, Fukuoka 820-8502, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Taira
authors.affiliation: Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, 680-4 Kawazu, Iizuka-shi, Fukuoka 820-8502, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Umei
authors.affiliation: Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, 680-4 Kawazu, Iizuka-shi, Fukuoka 820-8502, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Komatsu
authors.affiliation: Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, 680-4 Kawazu, Iizuka-shi, Fukuoka 820-8502, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakamoto
authors.affiliation: Department of Biochemistry & Biophysics, Texas A & M University, College Station, TX 77843-2128, United States.
authors.forename: Gulcin
authors.initials: G
authors.lastname: Gulten
authors.affiliation: Department of Biochemistry & Biophysics, Texas A & M University, College Station, TX 77843-2128, United States.
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
authors.affiliation: Department of Applied Chemistry, Kyushu Institute of Technology, 1-1 Sensui-cho, Tobata-ku, Kitakyushu-shi, Fukuoka 804-8550, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kitamura
authors.affiliation: Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, 680-4 Kawazu, Iizuka-shi, Fukuoka 820-8502, Japan; Biomedical Informatics Research and Development Center (BMIRC), Kyushu Institute of Technology, 680-4 Kawazu, Iizuka-shi, Fukuoka 820-8502, Japan. Electronic address: aokis@bio.kyutech.ac.jp.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Aoki
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000254:growth & development; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium
keywords: Antibiotics; Enoyl-acyl carrier protein reductase (InhA); In silico drug screening; Matched molecular pair (MMP); Mycobacterium tuberculosis