Integrating pharmacophore mapping, virtual screening, density functional theory, molecular simulation towards the discovery of novel apolipoprotein (apoE ε4) inhibitors

Abstract Aim An integrated protocol of virtual screening involving molecular docking, pharmacophore probing, and simulations was established to identify small novel molecules targeting crucial residues involved in the variant apoE e4 to mimic its behavior as apoE2 thereby eliminating the amyloid plaque accumulation and facilitating its clearance. Materials and Methods An excellent ligand-based and structure-based approach was made to identify common pharmacophoric features involving structure-based docking with respect to apoE e4 leading to the development of apoE e4 inhibitors possessing new scaffolds. An effort was made to design multiple-substituted triazine derivatives series bearing a novel scaffold. A structure-based pharmacophore mapping was developed to explore the binding sites of apoE e4 which was taken into consideration. Subsequently, virtual screening, ADMET, DFT searches were at work to narrow down the proposed hits to be forwarded as a potential drug likes candidates. Further, the binding patterns of the best-proposed hits were studied and were forwarded for molecular dynamic simulations of 10 ns for its structural optimization. Results Selectivity profile for the most promising candidates was studied, revealing significantly C13 and C15 to be the most potent compounds. The proposed hits can be forwarded for further study against apoE e4 involved in neurological disorder Alzheimer’s.