title: From carbohydrates to drug-like fragments: Rational development of novel α-amylase inhibitors.
abstract: Starch catabolism leading to high glucose level in blood is highly problematic in chronic metabolic diseases, such as type II diabetes and obesity. α-Amylase catalyzes the hydrolysis of starch, increasing blood sugar concentration. Its inhibition represents a promising therapeutic approach to control hyperglycaemia. However, only few drug-like molecule inhibitors without sugar moieties have been discovered so far, and little information on the enzymatic mechanism is available. This work aims at the discovery of novel small α-amylase binders using a systematic in silico methodology. 3D-pharmacophore-based high throughput virtual screening of small compounds libraries was performed to identify compounds with high α-amylase affinity. Twenty-seven compounds were selected and biologically tested, revealing IC50 values in the micromolar range and ligand efficiency higher than the one of the bound form of acarbose, which is used as a reference for α-amylase inhibition.
authors.affiliation: Freie Universität Berlin, Institute of Pharmacy, Department of Pharmaceutical & Medicinal Chemistry, Königin-Luise Str. 2-4, 14195 Berlin, Germany.
authors.forename: Jamil
authors.initials: J
authors.lastname: Al-Asri
authors.affiliation: University of Debrecen, Department of Inorganic & Analytical Chemistry, Egyetem ter 1, PO Box 21, H-4032 Debrecen, Hungary.
authors.forename: Erika
authors.initials: E
authors.lastname: Fazekas
authors.affiliation: University of Debrecen, Department of Inorganic & Analytical Chemistry, Egyetem ter 1, PO Box 21, H-4032 Debrecen, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Lehoczki
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.
authors.forename: Andrej
authors.initials: A
authors.lastname: Perdih
authors.affiliation: Freie Universität Berlin, Institute of Pharmacy, Department of Pharmaceutical & Medicinal Chemistry, Königin-Luise Str. 2-4, 14195 Berlin, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Görick
authors.affiliation: Freie Universität Berlin, Institute of Pharmacy, Department of Pharmaceutical & Medicinal Chemistry, Königin-Luise Str. 2-4, 14195 Berlin, Germany.
authors.forename: Matthias F
authors.initials: MF
authors.lastname: Melzig
authors.affiliation: University of Debrecen, Department of Inorganic & Analytical Chemistry, Egyetem ter 1, PO Box 21, H-4032 Debrecen, Hungary.
authors.forename: Gyöngyi
authors.initials: G
authors.lastname: Gyémánt
authors.affiliation: Freie Universität Berlin, Institute of Pharmacy, Department of Pharmaceutical & Medicinal Chemistry, Königin-Luise Str. 2-4, 14195 Berlin, Germany. Electronic address: gerhard.wolber@fu-berlin.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.affiliation: Freie Universität Berlin, Institute of Pharmacy, Department of Pharmaceutical & Medicinal Chemistry, Königin-Luise Str. 2-4, 14195 Berlin, Germany. Electronic address: jeremie.mortier@fu-berlin.de.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Mortier
mesh_terms: D002241:Carbohydrates / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D000516:alpha-Amylases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002241:Carbohydrates; D004791:Enzyme Inhibitors; D000516:alpha-Amylases
keywords: Fragment-based drug design; Hyperglycaemia; Obesity; Pharmacophore model; Type II diabetes; Virtual screening; α-Amylase inhibition