In silico identification and evaluation of potential interaction of Azadirachta indica phytochemicals with Plasmodium falciparum heat shock protein 90.

Plasmodium falciparum heat shock protein 90 (PfHsp90) has been investigated as a potential target of antimalarial drug action using naturally occurring compounds. In this study, we performed in silico screening of 236 phytochemicals of Azadirachta indica, a plant known to possess antimalarial activity, and identified fourteen (14) potential non-carcinogenic, non-mutagenic, non-teratogenic and non-genotoxic phytochemicals. These phytochemicals were docked into the ATP-binding site of PfHsp90 using Autodock vina, and docked poses were rescored using PLANTS ChemPlp, X-Score version 1.2 and NNScore version 2.0. Consensus analysis of the scores using rank-by-rank and rank-by-number and receptor-ligand interaction assessment using LigPlot, led to the identification of margolone, margolonone, nimbinone, nimbione, nimosone and sugiol as best ranked potential interacting partners of PfHsp90. Molecular dynamic simulations of PfHsp90-ligand complexes for the six phytochemicals were performed using NAMD 2.9. The RMSD analysis of simulations trajectories, the ligand interaction analysis of receptor-ligand complex, and the free energy of binding with MMPBSA.py script and Bennett's acceptance ratio method (BAR) confirmed that these six phytochemicals may have potential to functionally interact with PfHsp90. However, though sharing several similar interacting residues with standard control binders yet the higher number of hydrogen bonds, higher level of sustained stability during molecular dynamics simulations and better free energy of binding suggest that margolonone, nimbinone and nimbione may have higher functional interaction potential with PfHsp90. Therefore, these phytochemicals may serve as potential leads in antimalarial drug design and development.