Computational discovery of potent drugs to improve the treatment of pyrazinamide resistant Mycobacterium tuberculosis mutants

Journal of Cellular Biochemistry
Manaswini JagadebAvinash Sonawane

Abstract

Emergence of multi-drug resistance tuberculosis has become a serious health problem globally. Accumulation of mutations in the drug target led to the development of multi-drug resistant mycobacterial strains that have made most of the conventional drugs ineffective. Hence, there is desperate need for the development of new therapeutic strategies. Here, we focused on the analysis of mutations in Mycobacterium tuberculosis (Mtb) PncA (pyrazinamidase) that is responsible for resistance against first-line anti-tuberculosis pyrazinamide (PZA) drug. First, PZA and its two isoforms were analyzed for their binding affinity toward ligand binding cavity of Mtb wild-type and mutant PncA proteins. The observations suggested that some drug resistant mutations cause strong binding of PncA with the active form of PZA and impair its release, which is required to inhibit the growth of Mtb. To improve the treatment of PZA resistant Mtb, high throughput virtual drug screening was performed to identify potent drug molecules from a library of compounds derived from ChEMBL database. From this library, we predicted a lead molecule (terta-butyl(2S,4S)-4-amino-2-cyclopropyl-6-(trifluoromethyl)-3,4-dihydro-2H-quinoline-1-carboxylate) to be more effectiv...Continue Reading

References

Oct 15, 1996·FEMS Microbiology Letters·H TaniguchiS Yoshida
Mar 1, 1997·Antimicrobial Agents and Chemotherapy·S SreevatsanJ M Musser
Apr 4, 1997·Journal of Molecular Biology·G JonesR Taylor
Jun 11, 1998·Emerging Infectious Diseases·A RattanN Ahmad
Jul 2, 1999·Antimicrobial Agents and Chemotherapy·H J MarttilaM K Viljanen
Oct 20, 2001·Journal of Korean Medical Science·K W LeeK S Jung
Jul 1, 1963·Journal of Molecular Biology·G N RAMACHANDRANV SASISEKHARAN
Nov 26, 2003·Antimicrobial Agents and Chemotherapy·Glenn P MorlockRobert C Cooksey
Jul 24, 2004·Acta Crystallographica. Section D, Biological Crystallography·Alexander W Schüttelkopf, Daan M F van Aalten
Oct 8, 2005·Journal of Computational Chemistry·David Van Der SpoelHerman J C Berendsen
Aug 15, 2006·Nature Medicine·Catherine VilchèzeWilliam R Jacobs
Nov 1, 2006·Proceedings of the National Academy of Sciences of the United States of America·George D RoseAmos Maritan
Dec 22, 2006·Journal of Medicinal Chemistry·Stephen A Hitchcock, Lewis D Pennington
Jan 11, 2007·The Journal of Chemical Physics·Giovanni BussiMichele Parrinello
Mar 16, 2007·The Journal of Antimicrobial Chemotherapy·Raphael C Y ChanAugustine F B Cheng
Jun 24, 2009·Memórias do Instituto Oswaldo Cruz·R Zenteno-CuevasA Parissi
Mar 26, 2011·Biomolecular Concepts·Scott A Hollingsworth, P Andrew Karplus
Sep 29, 2011·Nucleic Acids Research·Anna GaultonJohn P Overington
Oct 11, 2011·Journal of Cheminformatics·Noel M O'BoyleGeoffrey R Hutchison
Jun 27, 2012·The Journal of Infectious Diseases·Jorge Barrios-PayánRogelio Hernandez-Pando
Feb 7, 2013·Journal of Biomolecular Structure & Dynamics·Vidya Rajendran, Rao Sethumadhavan
May 1, 2013·Nature Reviews. Drug Discovery·Alimuddin ZumlaStewart T Cole
May 23, 2015·PLoS Computational Biology·Erik van DijkSanne Abeln
Jul 29, 2015·PloS One·Michael G WhitfieldAnnelies van Rie
Oct 16, 2015·The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union Against Tuberculosis and Lung Disease·Y Zhang, W-W Yew
Jun 17, 2016·European Journal of Clinical Pharmacology·Roger K VerbeeckTim W Rennie
Nov 9, 2016·Lancet·Catherine BerryPhilipp du Cros
Oct 6, 2017·Journal of Cellular Biochemistry·Mansi AggarwalAbhinav Grover

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