title: Leishmania donovani pteridine reductase 1: biochemical properties and structure-modeling studies.
abstract: Pteridine reductase 1 (PTR1, EC 1.5.1.33) is a NADPH dependent short-chain reductase (SDR) responsible for the salvage of pterins in the protozoan parasite Leishmania. This enzyme acts as a metabolic bypass for drugs targeting dihydrofolate reductase, therefore, for successful antifolate chemotherapy to be developed against Leishmania, it must target both enzyme activities. Based on homology model drawn on recombinant pteridine reductase isolated from a clinical isolate of L. donovani, we carried out molecular modeling and docking studies with two compounds of dihydrofolate reductase specificity showing promising antileishmanial activity in vitro. Both the inhibitors appeared to fit well in the active pocket revealing the tight binding of the carboxylic acid ethyl ester group of pyridine moiety to pteridine reductase and identify the important interactions necessary to assist the structure based development of novel pteridine reductase inhibitors.
authors.affiliation: Drug Target Discovery and Development, Central Drug Research Institute, Chattat Manzil, P.O. Box No. 173, Lucknow 226001, India.
authors.forename: Pranav
authors.initials: P
authors.lastname: Kumar
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Kumar
authors.forename: Shyam Sundar
authors.initials: SS
authors.lastname: Verma
authors.forename: Namrata
authors.initials: N
authors.lastname: Dwivedi
authors.forename: Nasib
authors.initials: N
authors.lastname: Singh
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Siddiqi
authors.forename: Rama Pati
authors.initials: RP
authors.lastname: Tripathi
authors.forename: Anuradha
authors.initials: A
authors.lastname: Dube
authors.forename: Neeloo
authors.initials: N
authors.lastname: Singh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D001708:Biopterins / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000737:chemistry; D007893:Leishmania donovani / Q000187:drug effects / Q000201:enzymology*; D008727:Methotrexate / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D001708:Biopterins; D010088:Oxidoreductases; C085592:pteridine reductase; D008727:Methotrexate