title: α-Amylase Modulation: Discovery of Inhibitors Using a Multi-Pharmacophore Approach for Virtual Screening.
abstract: Better control of postprandial hyperglycemia can be achieved by delaying the absorption of glucose resulting from carbohydrate digestion. Because α-amylase initiates the hydrolysis of polysaccharides, the design of α-amylase inhibitors can lead to the development of new treatments for metabolic disorders such as type II diabetes and obesity. In this study, a rational computer-aided approach was developed to identify novel α-amylase inhibitors. Three-dimensional pharmacophores were developed based on the binding mode analysis of six different families of compounds that bind to this enzyme. In a stepwise virtual screening workflow, seven molecules were selected from a library of 1.4 million. Five out of seven biologically tested compounds showed α-amylase inhibition, and the two most potent compounds inhibited α-amylase with IC50values of 17 and 27 μm. The scaffold benzylideneacetohydrazide was shared by four of the discovered inhibitors, emerging as a novel drug-like non-carbohydrate fragment and constituting a promising lead scaffold for α-amylase inhibition.
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical & Medicinal Chemistry, Freie Universität Berlin, Königin-Luise Str. 2-4, 14195, Berlin, Germany.
authors.forename: Jamil
authors.initials: J
authors.lastname: Al-Asri
authors.affiliation: Department of Inorganic & Analytical Chemistry, University of Debrecen, Egyetem ter 1, PO Box 21, 4032, Debrecen, Hungary.
authors.forename: Gyöngyi
authors.initials: G
authors.lastname: Gyémánt
authors.affiliation: Department of Inorganic & Analytical Chemistry, University of Debrecen, Egyetem ter 1, PO Box 21, 4032, Debrecen, Hungary.
authors.forename: Erika
authors.initials: E
authors.lastname: Fazekas
authors.affiliation: Department of Inorganic & Analytical Chemistry, University of Debrecen, Egyetem ter 1, PO Box 21, 4032, Debrecen, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Lehoczki
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical & Medicinal Chemistry, Freie Universität Berlin, Königin-Luise Str. 2-4, 14195, Berlin, Germany.
authors.forename: Matthias F
authors.initials: MF
authors.lastname: Melzig
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical & Medicinal Chemistry, Freie Universität Berlin, Königin-Luise Str. 2-4, 14195, Berlin, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical & Medicinal Chemistry, Freie Universität Berlin, Königin-Luise Str. 2-4, 14195, Berlin, Germany.
authors.forename: Jérémie
authors.identifier: http://orcid.org/0000-0001-8707-3867
authors.initials: J
authors.lastname: Mortier
keywords: computer-aided drug design; diabetes; high-throughput virtual screening; lead discovery; obesity; α-amylase