title: Identification of novel acetylcholinesterase inhibitors through e-pharmacophore-based virtual screening and molecular dynamics simulations.
abstract: Alzheimer's disease (AD), a progressive neurodegenerative disorder is the most common cause of dementia among elderly people. To date, the successful therapeutic strategy to treat AD is maintaining the levels of acetylcholine via inhibiting acetylcholinesterase (AChE). The present study involves identification of newer AChE inhibitors by dual approach of e-pharmacophore and structure-based virtual screening of Asinex library. Robustness of docking protocol was validated by enrichment calculation with ROC value .71 and BEDROC value .028. Among 11 selected hits, ZINC72338524 with best MM-GBSA dG binding shows optimal range of CNS properties and ligand-AChE complex stability. Further, molecular dynamics study revealed its molecular interactions with Trp86, Phe338, and Tyr341 amino acid residues of catalytic anionic site and Tyr124, Ser125, and Trp286 amino acid residues of peripheral anionic site. Physicochemical properties and ADMET risk prediction indicates their potential in druggability and safety.
authors: a Department of Pharmacy, Central University of Rajasthan , Bandarsindri, Ajmer 305817 , Rajasthan , India.
authors: Ruchi
authors: R
authors: Malik
authors: a Department of Pharmacy, Central University of Rajasthan , Bandarsindri, Ajmer 305817 , Rajasthan , India.
authors: Bhanwar Singh
authors: BS
authors: Choudhary
authors: a Department of Pharmacy, Central University of Rajasthan , Bandarsindri, Ajmer 305817 , Rajasthan , India.
authors: Shubham
authors: S
authors: Srivastava
authors: a Department of Pharmacy, Central University of Rajasthan , Bandarsindri, Ajmer 305817 , Rajasthan , India.
authors: Pakhuri
authors: P
authors: Mehta
authors: b School of Pharmacy , Maharishi Markandeshwar University , Sadopur, Ambala 134007 , Haryana , India.
authors: Manish
authors: M
authors: Sharma
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000818:Animals; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D011485:Protein Binding
chemical_list: D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase
keywords: Alzheimer’s disease; E-pharmacophore; acetylcholinesterase; molecular dynamics; virtual screening