A new insights into the key structural features of plasmodium proteasome inhibitors using molecular modeling

The plasmodium proteasome is an emerging antimalarial target due to its essential role in all the major life cycle stages of the parasite and its contribution to the establishment of resistance to artemisinin (ART)-based therapies. A combination of molecular dynamic simulation, molecular docking and QSAR approaches was applied to elucidate the key structural features [1]. Molecular docking was performed to find correct conformations of plasmodium proteasome inhibitors. Molecular dynamics simulations validated the rationality of docking results and predicted the detailed interactions between the ligands and plasmodium proteasome [2]. The conformation with the lowest binding free energy was chosen to calculate molecular descriptors using MOE software. Some additional descriptors relevant to characterizing the structural properties of inclusion complexes were also calculated and used in QSAR model building. The final QSAR model, based on MLR, was characterized by satisfactory statistical parameters; calibration (R2c) and prediction (R2p) correlation coefficient of 0.89 and 0.71, respectively. An important hydrogen bond network was discovered though MD simulation. Some key residues (THR21, GLY23, LYS33, ALA49, THR300 and CYS307) were pointed out after the binding free energy calculation using MM-PBSA method. I hope results could provide useful information for our further design of potent plasmodium proteasome inhibitors.

Keywords:

Plasmodium proteasome , Antimalarial , Molecular dynamics , Molecular docking , QSAR