In silico screening, structure-activity relationship, and biologic evaluation of selective pteridine reductase inhibitors targeting visceral leishmaniasis.
In this study we utilized the concept of rational drug design to identify novel compounds with optimal selectivity, efficacy and safety, which would bind to the target enzyme pteridine reductase 1 (PTR1) in Leishmania parasites. Twelve compounds afforded from Baylis-Hillman chemistry were docked by using the QUANTUM program into the active site of Leishmania donovani PTR1 homology model. The biological activity for these compounds was estimated in green fluorescent protein-transfected L. donovani promastigotes, and the most potential analogue was further investigated in intracellular amastigotes. Structure-activity relationship based on homology model drawn on our recombinant enzyme was substantiated by recombinant enzyme inhibition assay and growth of the cell culture. Flow cytometry results indicated that 7-(4-chlorobenzyl)-3-methyl-4-(4-trifluoromethyl-phenyl)-3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-one (compound 7) was 10 times more active on L. donovani amastigotes (50% inhibitory concentration [IC(50)] = 3 μM) than on promastigotes (IC(50) = 29 μM). Compound 7 exhibited a K(i) value of 0.72 μM in a recombinant enzyme inhibition assay. We discovered that novel pyrimido[1,2-a]pyrimidin-2-one systems generated from the allyl amines afforded from the Baylis-Hillman acetates could have potential as a valuable pharmacological tool against the neglected disease visceral leishmaniasis.
Drug Target Discovery and Development Division, Central Drug Research Institute, Chattar Manzil Palace, Lucknow, India.
Jaspreet
J
Kaur
Pranav
P
Kumar
Sargam
S
Tyagi
Richa
R
Pathak
Sanjay
S
Batra
Prashant
P
Singh
Neeloo
N
Singh
D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D008264:Macrophages / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics; D021261:Parasitic Sensitivity Tests / Q000379:methods; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D010088:Oxidoreductases; C085592:pteridine reductase