Pteridine reductase 1 (PTR1) is a unique enzyme required for survival of Leishmania species, a causative organism for the disease Leishmaniasis. We herein report the design, docking and ADMET prediction studies of 2-substituted-5-[(6-substituted-1H-benzimidazol-2yl)methyl]azole derivatives (B1-B14) as PTR 1 inhibitors. Molecular docking studies showed good binding interaction of the compounds with the active site of the Pteridne reductase from L. major with compounds B5 and B12 showing docking scores of -61.5232 and -62.5897 respectively which were comparable with the original ligand, dihydrobiopterin. Large substituents on the azole ring as well as substitutions on 6th position of benzimidazole ring were found favorable for interaction with PTR1 active site. Physicochemical properties, bioactivity prediction and toxicity profiles of the compounds were studied using molinspiration and admetSAR web servers. All compounds followed Lipinskis rule of five and can be considered as good oral candidates. Bioactivity prediction indicated the compounds to be enzyme inhibitor thus the rationale of designing PTR 1 inhibitors was met. Most of the compounds were predicted to have good ADMET properties in terms of GI absorption, absence of P-glycoprotein interaction, and LD50 values in rats. The designed molecules can be further explored for their anti-leishmanial activity.
Keywords Pteridine Reductase 1, Leishmaniasis, benzimidazole derivatives, docking studies, ADMET, druglikeness.
Key words: Pteridine Reductase 1, Leishmaniasis, benzimidazole derivatives, docking studies, ADMET, drug likeness.
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