title: High throughput virtual screening and E-pharmacophore filtering in the discovery of new BACE-1 inhibitors.
abstract: Alzheimer's disease is a progressive neurodegenerative disorder, which is characterized by amyloid β peptide deposition in the brain. Aβ peptide, the major component of amyloid plaques is generated by the sequential processing of a larger protein called amyloid Precursor Protein by β-amyloid cleaving enzyme (BACE-1). In this study, we appllied computer assisted methodology unifying molecular docking and pharmacophore filtering to identify potent inhibitors against BACE-1. In order to inspect the pharmacophore region and binding mode of BACE-1 135 reported co-crystallized ligands of BACE-1 were docked into the active site using Glide XP. The present molecular docking studies provided critical information on protein ligand interactions that revealed imminent information on chemical features essential to inhibiting BACE-1. Based on the docking results we proposed structure based pharmacophore features that hold well as potent BACE-1 inhibitors. A huge set of compounds was docked into the active site of BACE-1 and the hits from the docking were filtered to match the chemical features of the pharmacophore model. The compounds resulting from the pharmacophore filtering were again re-docked into the active site of BACE-1 and the three hits bound well into the active sites and matched the pharmacophore models which were identified as possible potential inhibitors of BACE-1. Molecular dynamics simulation reveals that lead 3 shows constant RMSD and the number of hydrogen bonding with the protein among the identified three lead molecules.
authors.affiliation: Department of Bioinformatics, Alagappa University, Karaikudi 630004, Tamilnadu, India. mkbioinformatics@gmail.com
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Muthusamy
authors.forename: Kh Dhanachandra
authors.initials: KhD
authors.lastname: Singh
authors.forename: Sathishkumar
authors.initials: S
authors.lastname: Chinnasamy
authors.forename: Selvaraman
authors.initials: S
authors.lastname: Nagamani
authors.forename: Gopinath
authors.initials: G
authors.lastname: Krishnasamy
authors.forename: Chinnaiyan
authors.initials: C
authors.lastname: Thiyagarajan
authors.forename: Palanisamy
authors.initials: P
authors.lastname: Premkumar
authors.forename: Muthuswamy
authors.initials: M
authors.lastname: Anusuyadevi
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D062126:Databases, Chemical; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000494:pharmacology*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding / Q000187:drug effects; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D016282:Aspartic Acid Endopeptidases