In silico investigation of falcipain-2 inhibition by hybrid benzimidazole-thiosemicarbazone antiplasmodial agents: A molecular docking, molecular dynamics simulation, and kinetics study

Abstract

The emergence of artemisinin-resistant variants of Plasmodium falciparum necessitates the urgent search for novel antimalarial drugs. In this regard, an in silico study to screen antimalarial drug candidates from a series of benzimidazole-thiosemicarbazone hybrid molecules with interesting antiplasmodial properties and explore their falcipain-2 (FP2) inhibitory potentials has been undertaken herein. FP2 is a key cysteine protease that degrades hemoglobin in Plasmodium falciparum and is an important biomolecular target in the development of antimalarial drugs. Pharmacokinetic properties, ADMET profiles, MM/GBSA-based binding free energies, reaction mechanisms, and associated barrier heights have been investigated. DFT, molecular dynamics simulation, molecular docking, and ONIOM methods were used. From the results obtained, four 4 N -substituted derivatives of the hybrid molecule ( E )-2-(1-(5-chloro-1 H -benzo[ d ]imidazol-2-yl)ethylidene)hydrazine-1-carbothioamide (1A) denoted 1B, 1C, 1D, and 1E are drug-like and promising inhibitors of FP2, exhibiting remarkably small inhibitory constants (5.94 × 10 –14 − 2.59 × 10 –04 M) and favorable binding free energies (−30.32 to −17.17 kcal/mol). Moreover, the ONIOM results have revealed that 1B and possibly 1C and 1D may act as covalent inhibitors of FP2. The rate-determining step of the thermodynamically favorable covalent binding mechanism occurs across a surmountable barrier height of 24.18 kcal/mol in water and 28.42 kcal/mol in diethyl ether. Our findings are useful for further experimental investigations on the antimalarial activities of the hybrid molecules studied. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11030-022-10594-3.

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