Identification of novel peptide inhibitors of Plasmodium falciparum dihydrofolate reductase (PfDHFR): molecular docking and MD simulation studies

The presence of drug-resistant variants of Plasmodium parasites within the population has presented a substantial obstacle to the eradication of Malaria. As a result, numerous research groups have directed their efforts towards creating new medication candidates that specifically target parasites. In this study, our main objective was to identify tri-peptide inhibitors for Plasmodium falciparum Dihydrofolate Reductase (PfDHFR) with the aim of finding a new peptide that exhibits superior binding properties compared to the current inhibitor, WR99210. In order to achieve this objective, a virtual library consisting of 8000 tripeptides was generated and subjected to computational screening against wild-type PfDHFR. The purpose of this screening was to discover the most effective binders at the active site. The four most optimal tripeptides identified (Trp-Trp-Glu, Trp-Phe-Tyr, Phe-Trp-Trp, Tyr-Trp-Trp) exhibited significant non-covalent interactions inside the active site of PfDHFR and had binding energies ranging from -9.5 to -9.0 kcal/mol and WR99210 had a binding energy of -6.2 kcal/mol. A 250 ns Molecular Dynamics (MD) simulation was performed to investigate the kinetic and thermodynamic characteristics of the protein-ligand complexes. The Root Mean Square Deviation (RMSD) values for the optimal tripeptides fell within the allowed range, indicating the stability of the ligands inside the protein complex. The K-i value for the most effective tripeptide was 0.3482 mu M, whereas WR99210 had a K-i value of 1.02 mu M. This article presents the initial discovery of peptide inhibitors targeting PfDHFR. In this text, we provide a comprehensive explanation of the interactions that occur between peptides and the enzyme.