Computational identification of aspartic protease inhibitors for antimalarial drug development against Plasmodium Vivax

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Detalles Bibliográficos
Publicado en:	Scientific Reports (Nature Publisher Group) vol. 15, no. 1 (2025), p. 14824-14844
Autor principal:	Alruwaili, Muharib
Otros Autores:	Alhassan, Hassan H., Almutary, Hayfa, Tahir ul Qamar, Muhammad
Publicado:	Nature Publishing Group
Materias:	Infections Software Public health Antiparasitic agents Parasitic diseases Secondary structure Optimization Hydrogen Proteinase inhibitors Drug development Proteases Computer applications Energy Metabolism Systems stability Chloroquine Protease inhibitors Drug resistance Malaria Proteins Simulation Aspartic endopeptidase Antimalarial agents Parasites Clinical trials Free energy Pharmacokinetics Ligands Protein structure Vector-borne diseases Natural products Rigidity Social
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Descripción
Resumen:	Malaria is a parasitic disease that has caused suffering to humans since ancient times and remains a major public health concern in tropical and subtropical regions.The development of novel antimalarials therefore becomes of utmost importance by targeting aspartic protease. The computational study utilized a molecular docking approach to identify hit compounds. In this study a molecular docking approach was employed to identify potential hit compounds. The molecular docking analysis yielded three hit compounds CMNPD229, ZINC000000018635, and ZINC000005425464 along with the reference drug chloroquine, with binding energy scores of -8.1 kcal/mol, -8.0 kcal/mol, -7.8 kcal/mol, and − 6.8 kcal/mol, respectively. Subsequently density function theory (DFT) was performed. Afterward, the protein-ligand (PL) complexes were subjected to molecular dynamic simulation (MDS) to identify the stability and rigidity of the complexes in a fleeting and dynamic setting. The complex CMNPD229 exhibited good stability followed by ZINC000000018635, ZINC000005425464, and the Control. The compounds showed good MM-PBSA/GBSA, WaterSwap, and entropy energy values. The calculated MM-PBSA/GBSA binding free energy scores were − 120.78 kcal/mol, -107.16 kcal/mol, -91.00 kcal/mol, and − 97.49 kcal/mol for CMNPD229, ZINC000000018635, ZINC000005425464, and the reference drug, respectively.Additionally, salt bridge analysis and secondary structure evaluation revealed that CMNPD229 formed the highest number of interactions (Glu290-Arg23 and Glu305-Lys306), indicating its stability as a potential drug candidate. This study suggests that CMNPD229 holds promise as a potent antimalarial drug by effectively inhibiting Plasmodium falciparum and Plasmodium vivax aspartic proteases.
ISSN:	2045-2322
DOI:	10.1038/s41598-025-98516-9
Fuente:	Science Database