Docking-Based Virtual Screening to Identify the Cysteine Protease Falcipain-2 Inhibitors of Plasmodium falciparum

Abstract

Malaria is an infectious disease caused by Plasmodium protozoan parasites that transmit via the female Anopheles sp. mosquito. Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi are the five Plasmodium species known to infect humans. P. falciparum is the most virulent species, causing the most deaths worldwide. The decrease in efficacy of most antimalarials suggests drug resistance. Therefore, the development of new effective antimalarials, particularly against novel targets, was still required. Cysteine protease falcipain-2 (CPF-2) plays a role in hemoglobin degradation; therefore, inhibiting the activity of this enzyme could be a viable antimalarial target. This study aimed to identify a potential inhibitor for the CPF-2 with PDB ID 3BPF from the ZINC15 database for treating malaria. This study employs a virtual screening workflow with HTVS, SP, and XP docking methods on the Glide Maestro Schrodinger. Based on the glide XP docking score, 10 hit compounds were identified, and their conformational interactions with CPF-2 were compared to the natural ligand (E-64). The binding energy values of hit compounds vary from -7.131 kcal/mol to -8.074 kcal/mol, which is more negative than the E-64 (-6.011 kcal/mol). The three best compounds identified from the ZINC15 database are ZINC000025691540, ZINC000096436101, and ZINC000097797430. All the hit compounds discovered similar interaction with E-64, specifically on the CPF-2 binding pocket residues with Gln36, Cys42, Gly83, Asn173, and His174. All hit compounds exhibit suitable Lipinski rule profiles and are potentially evaluated experimentally as CPF-2 enzyme inhibitor candidates.

Keywords: cysteine protease falcipain-2, malaria, molecular docking, Plasmodium falciparum, virtual screening