title: Probing the structure of Leishmania major DHFR TS and structure based virtual screening of peptide library for the identification of anti-leishmanial leads.
abstract: Leishmaniasis, a multi-faceted ethereal disease is considered to be one of the World's major communicable diseases that demands exhaustive research and control measures. The substantial data on these protozoan parasites has not been utilized completely to develop potential therapeutic strategies against Leishmaniasis. Dihydrofolate reductase thymidylate synthase (DHFR-TS) plays a major role in the infective state of the parasite and hence the DHFR-TS based drugs remains of much interest to researchers working on Leishmaniasis. Although, crystal structures of DHFR-TS from different species including Plasmodium falciparum and Trypanosoma cruzi are available, the experimentally determined structure of the Leishmania major DHFR-TS has not yet been reported in the Protein Data Bank. A high quality three dimensional structure of L.major DHFR-TS has been modeled through the homology modeling approach. Carefully refined and the energy minimized structure of the modeled protein was validated using a number of structure validation programs to confirm its structure quality. The modeled protein structure was used in the process of structure based virtual screening to figure out a potential lead structure against DHFR TS. The lead molecule identified has a binding affinity of 0.51 nM and clearly follows drug like properties.
authors.affiliation: Department of Computer Science and Computer Engineering, La Trobe University, Melbourne, Victoria, 3086, Australia.
authors.forename: Rajalakshmi
authors.initials: R
authors.lastname: Rajasekaran
authors.forename: Yi-Ping Phoebe
authors.initials: YP
authors.lastname: Chen
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000981:Antiprotozoal Agents / Q000032:analysis* / Q000494:pharmacology*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006860:Hydrogen Bonding / Q000187:drug effects; D018320:Leishmania major / Q000187:drug effects / Q000201:enzymology*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D019151:Peptide Library; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry*; D013816:Thermodynamics; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D014584:User-Computer Interface
chemical_list: D000596:Amino Acids; D000981:Antiprotozoal Agents; D008024:Ligands; D009097:Multienzyme Complexes; D019151:Peptide Library; C056930:thymidylate synthase-dihydrofolate reductase; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase