validation of novel inhibitors of malarial aspartyl protease, plasmepsin V and antimalarial efficacy prediction.

Plasmepsin V (Plm V) is an essential aspartic protease required for survival of the malaria parasite, . Plm V is required for cleaving the PEXEL motifs of many proteins and its inhibition leads to a knockout effect, indicating its suitability as potential drug target. To decipher new inhibitors of Plm V, molecular docking of four HIV-1 protease inhibitors active against PlmV was performed on Glide module of Schrödinger suite that supported saquinavir as a lead drug, and therefore, selected as a control. Saquinavir contains an important hydroxyethylamine (HEA) pharmacophore, which was utilized as backbone coupled with piperazine scaffold to build new library of compounds. Newly designed HEA compounds were screened virtually against Plm V. Molecular docking led to a few hits ( and ) with higher docking score over the control drug. Notably, compound showed the highest docking score (-11.90 kcal/mol) and XP Gscore (-11.948 kcal/mol). The Prime MMGBSA binding free energy for compound (-60.88 kcal/mol) and (-50.96 kcal/mol) was higher than saquinavir (-37.51 kcal/mol). The binding free energy for the last frame of molecular dynamic simulation supported compound (-92.88 kcal/mol) as potent inhibitor of Plm V over saquinavir (-72.77 kcal/mol), and thus, deserves experimental validations in culture and subsequently in animal models.Communicated by Ramaswamy H. Sarma.