Goyal_2014_J.Mol.Model_20_2099

Leishmaniasis is an endemic disease caused by infection with one of several different species of protozoan parasite Leishmania. Oligopeptidase B (OPB) is a serine peptidase which plays a vital role in survival of the Leishmania parasite in the host (human) macrophage and help in attaining complete virulence. Inhibition of this peptidase would check the parasite growth inside the host organism and would thus control its infection. Lack of efficient and cheap drugs has led to an urgent need for development of new anti-leishmanial drugs and this study is a step forward in this direction. Using a structure-based approach we virtually screened a large naturally-occurring compound library against OPB and subjected two top scoring compounds with high binding affinity to molecular dynamics simulations which showed a stable RMSD trajectory. The first compound COP (Glide score: -13.183) was found stable for 15 ns at RMSD of 2.5 A while the second compound TOA (Glide score: -10.308) was stable for 8 ns at RMSD of 1.5 A. The screened compounds interacted with some crucial residues of OPB such as COP interacted with Ser577 and His697 (part of the catalytic triad), Tyr499 (responsible for substrate stability), Arg576 (conserved in protozoan family) and Arg664 (plays a role in stabilization of the bound inhibitor). TOA also interacted with Glu669 (conserved in protozoan family) in addition to the residues interacted with COA. These interactions are crucial for OPB inhibition. This study identified naturally-occurring compound leads against OPB with good binding affinity and low toxicity to human cells.