title: Structure-based in-silico rational design of a selective peptide inhibitor for thymidine monophosphate kinase of mycobacterium tuberculosis.
abstract: Tuberculosis still remains one of the most deadly infectious diseases. The emergence of drug resistant strains has fuelled the quest for novel drugs and drug targets for its successful treatment. Thymidine monophosphate kinase (TMPK) lies at the point where the salvage and de novo synthetic pathways meet in nucleotide synthesis. TMPK in M.tb has emerged as an attractive drug target since blocking it will affect both the pathways involved in the thymidine triphosphate synthesis. Moreover, the unique differences at the active site of TMPK enzyme in M.tb and humans can be exploited for the development of ideal drug candidates. Based on a detailed evaluation of known inhibitors and available three-dimensional structures of TMPK, several peptidic inhibitors were designed. In silico docking and selectivity analysis of these inhibitors with TMPK from M.tb and human was carried out to examine their differential binding at the active site. The designed tripeptide, Trp-Pro-Asp, was found to be most selective for M.tb. The ADMET analysis of this peptide indicated that it is likely to be a drug candidate. The tripeptide so designed is a suitable lead molecule for the development of novel TMPK inhibitors as anti-tubercular drugs.
authors.affiliation: Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.forename: Sujata
authors.initials: S
authors.lastname: Sharma
authors.forename: Alagiri
authors.initials: A
authors.lastname: Srinivasan
authors.forename: Tej P
authors.initials: TP
authors.lastname: Singh
authors.forename: Punit
authors.initials: P
authors.lastname: Kaur
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000201:enzymology; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D013942:Thymine Nucleotides / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D013942:Thymine Nucleotides; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; C024157:thymidine 5'-triphosphate