Leishmania donovani pteridine reductase 1: biochemical properties and structure-modeling studies.
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.
Kumar
Pranav
P
Drug Target Discovery and Development, Central Drug Research Institute, Chattat Manzil, P.O. Box No. 173, Lucknow 226001, India.
Kumar
Ashutosh
A
Verma
Shyam Sundar
SS
Dwivedi
Namrata
N
Singh
Nasib
N
Siddiqi
Mohammad Imran
MI
Tripathi
Rama Pati
RP
Dube
Anuradha
A
Singh
Neeloo
N
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
D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D001708:Biopterins; D010088:Oxidoreductases; C085592:pteridine reductase; D008727:Methotrexate