Indonesian herbal compounds as potential inhibitors of Plasmodium falciparum CDPK2: Insights from docking, molecular dynamics, and DFT analysis

Context: Malaria remains a severe global health concern, exacerbated by increasing resistance to antimalarial agents in Plasmodium falciparum. Indonesian medicinal plants have demonstrated pharmacological potential, although their application against the calcium-dependent protein kinase 2 (CDPK2) of P. falciparum has not been previously explored. Aims: To assess the potential of Indonesian herbal compounds as inhibitors of P. falciparum CDPK2 using a range of in silico computational techniques. Methods: The structure of CDPK2 was retrieved from the Protein Data Bank (PDB ID: 4MVF) and prepared using the YASARA software. Structural validation was performed using Ramachandran plot analysis, ERRAT, and Verify 3D. The ligands were derived from documented Indonesian herbal compounds. Molecular docking was performed using AutoDock Vina integrated within YASARA, and the best-scoring ligands were subjected to DFT calculations using ORCA 5.0. ADME and biological activity predictions were performed using SwissADME and PASS, respectively. The stability of the most promising complex was assessed via normal mode analysis (NMA) using iMODS. Results: Among the screened compounds, epicatechin 3-O-(3-O-methylgallate) and remerin exhibited the highest binding affinities. While DFT analysis confirmed favorable electronic properties for both, remerin alone met the drug-likeness criteria based on ADME evaluation. Normal mode analysis demonstrated that the CDPK2-remerin complex maintained its structural stability throughout the simulation. Conclusions: Remerin was identified as a promising inhibitor of CDPK2 based on its binding affinity, pharmacokinetic properties, and molecular dynamics stability. Further in vitro and in vivo investigations are required to validate these findings.