title: Pharmacophore based 3D-QSAR modeling, virtual screening and docking for identification of potential inhibitors of β-secretase.
abstract: The enzyme β-secretase-1 is responsible for the cleavage of the amyloid precursor protein, a vital step in the process of the formation of amyloid-β peptides which are known to lead to neurodegeneration causing Alzheimer's disease. Challenges associated with toxicity and blood brain permeation inability of potential inhibitors, continue to evade a successful therapy, thus demanding the search and development of highly active and effective inhibitors. Towards these efforts, we used a ligand based pharmacophore model generation from a dataset of known inhibitors whose activities against β-secretase hovered in the nano molar range. The identified 5 feature pharmacophore model, AHHPR, was validated via three dimensional quantitative structure activity relationship as indicated by r2, q2and Pearson R values of 0.9013, 0.7726 and 0.9041 respectively. For a dataset of compounds with nano molar activity, the important pharmacophore features present in the current model appear to be similar with those observed in the models resulting from much wider activity range of inhibitors. Virtual screening of the ChemBridge CNS-Set™, a database having compounds with a better suitability for central nervous system based disorders followed by docking and analysis of the ligand protein interactions resulted in the identification of eight prospective compounds with considerable diversity. The current pharmacophore model can thus be useful for the identification, design and development of potent β-secretase inhibitors which by optimization can be potential therapeutics for Alzheimer's disease.
authors.affiliation: Department of Biological Sciences, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Hyderabad 500078, Telangana, India.
authors.forename: Ravichand
authors.initials: R
authors.lastname: Palakurti
authors.affiliation: Department of Biological Sciences, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Hyderabad 500078, Telangana, India. Electronic address: vrk@hyderabad.bits-pilani.ac.in.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Vadrevu
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer’s disease; Amyloid-β; Docking; Pharmacophore; QSAR; Virtual screening; β-secretase