In Silico design of Isoindolinone-Hydrazide hybrid compounds as antiplamodium through molecular docking, molecular dynamics simulation, and MM-PBSA calculation

Abstract

Malaria remains a major global health issue due to the emergence of drug-resistant Plasmodium falciparum . The discovery of new compounds targeting essential enzymes such as P. falciparum lactate dehydrogenase (PfLDH) and P. falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is a potential strategy for the development of antimalarials. In this study, 30 Isoindolinone-Hydrazide hybrid compounds were designed and evaluated using in silico molecular docking, molecular dynamics simulations, and MM-PBSA analysis. The molecular docking showed that all compounds exhibited stronger interactions than the native ligands of each protein. In PfLDH, the top three compounds ( 1e, 1l , and 1t ) showed binding energies ranging from -8.3 to -8.6 kcal/mol, more favorable than the native ligand (-5.7 kcal/mol). In PfDHFR-TS, compounds 1k and 1l have the best affinity with binding energies of -11.1 and -10.8 kcal/mol, better than the native ligand (-8.1 kcal/mol). Molecular dynamics simulations indicate that the 1l -PfLDH and 1k -PfDHFR-TS complex provides the best stability of protein interactions and structure, characterized by low Rg values, minimal RMSD fluctuations, and stable RMSF patterns in key residues. Physicochemical analysis confirms that all compounds comply with Lipinski's rules, supporting their candidacy as drug-like molecules. This computational investigation identifies Isoindolinone-Hydrazide hybrids, particularly compounds 1l (for PfLDH) and 1k (for PfDHFR-TS), as promising in silico antimalarial inhibitor candidates. These findings provide a theoretical basis for future experimental validation to confirm their predicted antiplasmodial potential.

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