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 ε4 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 ε4 leading to the development of apoE ε4 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 ε4 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 ε4 involved in neurological disorder Alzheimer's.
journal_name
Comput Biol Chemjournal_title
Computational biology and chemistryauthors
Johari S,Sharma A,Sinha S,Das Adoi
10.1016/j.compbiolchem.2018.12.013subject
Has Abstractpub_date
2019-04-01 00:00:00pages
83-90eissn
1476-9271issn
1476-928Xpii
S1476-9271(18)30838-7journal_volume
79pub_type
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