4.7 Article

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

Journal

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Volume 40, Issue 18, Pages 8352-8364

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2021.1911855

Keywords

In silico; drug design; plasmepsin; antimalarial

Funding

  1. Department of Science and Technology [DST/TDT/DDP-14/2018]
  2. Act 211 Government of the Russian Federation [02.A03.21.0011]
  3. Ministry of Science and Higher Education of Russia [FENU-2020-0019]
  4. DBT
  5. CSIR, Govt. of India

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Plasmepsin V is an essential protease for the survival of the malaria parasite Plasmodium falciparum, with inhibition showing potential as a drug target. Through molecular docking, a new compound has been identified as a potent inhibitor, which warrants further experimental validation.
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 Schrodinger 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

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