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

Abstract

Plasmepsin V (Plm V) is an essential aspartic protease required for survival of the malaria parasite, Plasmodium falciparum (Pf). Plm V is required for cleaving the PEXEL motifs of many Pf proteins and its inhibition leads to a knockout effect, indicating its suitability as potential drug target. To decipher new inhibitors of PfPlm V, molecular docking of four HIV-1 protease inhibitors active against PfPlmV 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 (1 and 3) with higher docking score over the control drug. Notably, compound 1 showed the highest docking score (–11.90 kcal/mol) and XP Gscore (–11.948 kcal/mol). The Prime MMGBSA binding free energy for compound 1 (–60.88 kcal/mol) and 3 (–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 1 (–92.88 kcal/mol) as potent inhibitor of PfPlm V over saquinavir (–72.77 kcal/mol), and thus, deserves experimental validations in culture and subsequently in animal models.

Communicated by Ramaswamy H. Sarma

Keywords:

• In silico
• drug design
• plasmepsin
• antimalarial

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by Department of Science and Technology (DST/TDT/DDP-14/2018) and by Act 211 Government of the Russian Federation, contract 02.A03.21.0011 and by the Ministry of Science and Higher Education of Russia (Grant FENU-2020-0019). PPS acknowledges DBT for junior research fellowship, SK is grateful to CSIR, Govt. of India for senior research fellowship.