Abstract
InhA or enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis (mtInhA), which controls mycobacterial cell wall construction, has been targeted in the development of antituberculosis drugs. Previously, our in silico structure-based drug screening study identified a novel class of compounds (designated KES4), which is capable of inhibiting the enzymatic activity of mtInhA, as well as mycobacterial growth. The compounds are composed of four ring structures (A-D), and the MD simulation predicted specific interactions with mtInhA of the D-ring and methylene group between the B-ring and C-ring; however, there is still room for improvement in the A-ring structure. In this study, a structure-activity relationship study of the A-ring was attempted with the assistance of in silico docking simulations. In brief, the virtual chemical library of A-ring-modified KES4 was constructed and subjected to in silico docking simulation against mtInhA using the GOLD program. Among the selected candidates, we achieved synthesis of seven compounds, and the bioactivities (effects on InhA activity and mycobacterial growth and cytotoxicity) of the synthesized molecules were evaluated. Among the compounds tested, two candidates (compounds 3d a...Continue Reading
References
Jan 1, 1995·Annual Review of Biochemistry·P J Brennan, H Nikaido
Jul 4, 1995·Biochemistry·A QuémardJ S Blanchard
Jan 6, 1995·Journal of Molecular Biology·G JonesR C Glen
Jan 14, 1994·Science·A BanerjeeW R Jacobs
Apr 4, 1997·Journal of Molecular Biology·G JonesR Taylor
Feb 27, 1999·Antimicrobial Agents and Chemotherapy·L M McMurryS B Levy
Jun 27, 2000·Journal of Bacteriology·C VilchèzeW R Jacobs
Jun 28, 2000·Biochemistry·S L ParikhP J Tonge
May 28, 2003·Journal of Chemical Information and Computer Sciences·Jean-Loup FaulonRamdas S Pophale
May 2, 2006·Journal of Molecular Biology·Jaim S OliveiraDiógenes S Santos
Oct 13, 2006·Journal of Medicinal Chemistry·Xin HePaul R Ortiz de Montellano
Mar 10, 2007·Current Topics in Medicinal Chemistry·Peter J TongeRichard A Slayden
Apr 2, 2009·Environmental Health Perspectives·Cathy A LaetzNathaniel L Scholz
May 15, 2010·Science·Christopher Dye, Brian G Williams
May 22, 2010·Lancet·Knut LönnrothMario C Raviglione
May 22, 2010·Lancet·Pamela Das, Richard Horton
Aug 11, 2010·European Journal of Medicinal Chemistry·Tamara DelaineJean Bernadou
Dec 15, 2010·Molecular Microbiology·Virginie MolleLaurent Kremer
Jan 15, 2013·European Journal of Medicinal Chemistry·Yuji KosekiShunsuke Aoki
Apr 23, 2013·Journal of Chemical Information and Modeling·Tomohiro KinjoShunsuke Aoki
Nov 19, 2013·Current Topics in Medicinal Chemistry·Yuji Koseki, Shunsuke Aoki
Mar 25, 2014·Journal of Chemical Information and Modeling·Maiko KobayashiShunsuke Aoki
Dec 3, 2014·European Journal of Medicinal Chemistry·Mariane RottaPablo Machado
Jan 13, 2015·Cold Spring Harbor Perspectives in Medicine·Giovanni SotgiuGiovanni Battista Migliori
Mar 18, 2015·European Journal of Medicinal Chemistry·Hironori KanetakaShunsuke Aoki
Oct 31, 2015·Lancet·Pamela Das, Richard Horton
Jun 1, 2017·International Journal of Mycobacteriology·Junichi TairaShunsuke Aoki
Sep 28, 2017·The Journal of Antibiotics·Junichi TairaShunsuke Aoki