title: In silico structure-based design of a novel class of potent and selective small peptide inhibitor of Mycobacterium tuberculosis Dihydrofolate reductase, a potential target for anti-TB drug discovery.
abstract: The worldwide TB structural genomics initiative has identified several new drug targets for Mycobacterium tuberculosis (M. tb). Dihydrofolate reductase (DHFR) catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate that is essential for DNA synthesis. Inhibition of its activity leads to arrest of DNA synthesis and hence cell death. Thus, M. tb DHFR (mtDHFR) is an attractive novel drug target for developing anti-TB drugs. Structural comparison of mtDHFR and human DHFR (hDHFR) reveals key differences in the active sites. These differences can be exploited for the design of selective inhibitors for mtDHFR. Based on the recently determined high resolution crystal structure of mtDHFR complexed with known inhibitor methotrexate (MTX) and cofactor NADPH, a tri-peptide inhibitor has been identified using a structure-based drug design approach. Docking studies indicate that the designed tripeptide inhibitor has a high potency (K (d) = 1.78 nM) and is a selective (approximately 120 fold over hDHFR) inhibitor for mtDHFR. Hence, the tripeptide is a suitable lead compound for the development of novel anti-TB drugs.
authors.affiliation: Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.forename: Rajakrishnan
authors.initials: R
authors.lastname: Vijayakrishnan
authors.forename: Gita
authors.initials: G
authors.lastname: Subba Rao
mesh_terms: D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D018360:Crystallography, X-Ray; D015195:Drug Design; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding / Q000187:drug effects; D008024:Ligands; D008727:Methotrexate / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D009952:Ornithine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000145:classification* / Q000494:pharmacology*; D011622:Pterins / Q000737:chemistry / Q000494:pharmacology; D015203:Reproducibility of Results; D013379:Substrate Specificity / Q000187:drug effects; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D005493:Folic Acid Antagonists; D008024:Ligands; D010455:Peptides; D011622:Pterins; D014227:Triazines; C085590:N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine; C006201:BRL 6231; D009952:Ornithine; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate
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