MOLECULAR MODELING STUDIES OF BENZIMIDAZOLYL-CHALCONES AS ANTILEISHMANIAL AGENTS USING QSAR, DOCKING, ADME AND MOLECULAR DYNAMICS STUDIES

Introduction: Present leishmaniasis treatment regimen has many limitations including severe adverse effects, toxicity, and Leishmania strains resistance. In the present study, the objective is to perform QSAR, molecular docking and ADME prediction studies on benzimidazolylchalcones in order to select an antileishmanial drug candidate.Materials & methods: QSAR models were performed on 12 benzimidazolylchalcones with antileishmanial activities against promastigote strains of L. donovani. Binding free energy calculations were performed using MM-GBSA to assess the affinity of the ligands for the proteins. In addition, the three most active compounds (4a-c, IC50 <1-μM) were docked with the protein phosphodiesterase B1 (PDB ID: 2JK6).Results and Discussion: The optimum model has squared correlation coefficient (R2) of 0.983, and leave-one-out (LOO) cross-validation coefficient (Q2CV) value of 0.942. The number of descriptors involved in the model is acceptable (R2 - Q2CV = 0.041), which confirms the model’s stability and validates the developed model’s predictive power. Docking studies revealed that the best compound 4c formed hydrogen bond with SER 464, pi-cation contact with LYS 61 and hydrophobic interactions with LEU 62, TYR 64 and LEU72 of the active site of L. donovani phosphodiesterase B1. ADME properties results showed that all three molecules have good pharmacokinetic properties.Conclusion: Finally, molecular dynamics simulation studies at 30 ns revealed stable interactions with the 2JK6 protein. This study validates the choice of the ortho-chlorinated derivative of benzimidazolylchalcones as the lead compound for developing new derivatives with optimized antileishmanial properties.