In-silico identification of antimalarial compounds targeting PfMDR1 of Plasmodium falciparum

PfMDR1, a key transporter protein in Plasmodium falciparum, contributes to antimalarial drug resistance by actively expelling drugs like chloroquine from the parasite's digestive vacuole, lowering their intracellular efficacy. In this study, our aim was to identify the antimalarial compounds with unknown targets on the basis of cellular assays from the Chembl and IUPHAR databases against the target protein PfMDR1, having PDB ID: 8JWI, using molecular docking with GLIDE and GOLD. The top-ranking compound demonstrated a GLIDE docking score of - 12.169 kcal/mol, surpassing the benchmark compound (- 5.435 kcal/mol) and other experimentally tested drugs. Post-docking analyses using LigPlot and PyMOL revealed strong hydrogen bonding and hydrophobic interactions with key active site residues. Binding affinity predictions using X-SCORE further supported the superior binding of the top compound. To evaluate stability and inhibitory potential, we performed molecular dynamics (MD) simulations using GROMACS, analyzing protein-ligand interactions throughout the trajectory. The top compound maintained stable binding throughout the simulation, with minimal fluctuations. The binding free energy calculations using MM/PBSA method further confirmed its inhibitory effect, with a binding free energy of - 130.971 ± 14.283 kJ/mol, significantly higher as compared to the benchmark and other experimentally tested compounds, indicating stronger and more stable interactions. These findings suggest that the identified inhibitor exhibits greater potency against PfMDR1 than the benchmark and other screened antimalarial drugs, making it a promising candidate for overcoming P. falciparum drug resistance. This study provides valuable insights for future structure-based drug design targeting PfMDR1 and developing next-generation antimalarial therapies.

The online version contains supplementary material available at 10.1007/s40203-025-00486-3.