title: Fragment-based designing for the generation of novel leads against BACE1.
abstract: BACE1, the aspartate protease that generates amyloid-β peptide (Aβ) in the brain of AD (Alzheimer's disease) patients, has emerged as a pharmaceutically relevant target. Here, a fragment-based in silico approach has been adopted to design novel compounds with increased ligand efficiency for BACE1, before screening for brain permeability and toxicity. Fragments docked to the active site of BACE1 and sorted into two groups using binding energy cut-off, were joined to create novel ligands with binding energy lying in the range between -11.36 kcal/mol and -8.56 kcal/mol. Interestingly, QIN, a known inhibitor of BACE1 with an IC50 of 11nM, when docked to BACE1, shows a binding energy (-9.43 kcal/mol) lying within the range of the novel ligand-BACE1 complexes. The present strategy thus enabled the design of four novel inhibitors of BACE1 with favourable binding energy, brain permeability and no toxicity that might show promise as leads in future.
authors.forename: Sucharita
authors.initials: S
authors.lastname: Das
authors.forename: Sandipan
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700 019, India. soumalee@gmail.com.
authors.forename: Soumalee
authors.initials: S
authors.lastname: Basu
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human