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

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 stuyda 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. These compounds were further to assess their potential as optimal drug candidates. 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.