title: Receptor- and ligand-based study on novel 2,2'-bithienyl derivatives as non-peptidic AANAT inhibitors.
abstract: Arylalkylamine N-acetyl transferase (serotonin N-acetyl transferase, AANAT) is a critical enzyme in the light-mediated regulation of melatonin production and circadian rythm. With the objective of discovering new chemical entities with inhibitory potencies against AANAT, a medium-throughput screening campaign was performed on a chemolibrary. We found a class of molecules based on a 2,2'-bithienyl scaffold, and compound 1 emerged as a first hit. Herein, we describe our progress from hit discovery and to optimization of this new class of compounds. To complete the study, computational approaches were carried out: a docking study which provided insights into the plausible binding modes of these new AANAT inhibitors and a three-dimensional quantitative structure-activity relationship study that applied comparative molecular field analysis (CoMFA) methodology. Several CoMFA models were developed (variable alignments and options), and the best predictive one yields good statistical results (q(2) = 0.744, r(2) = 0.891, and s = 0.273). The resulting CoMFA contour maps were used to illustrate the pharmacomodulations relevant to the biological activities in this series of analogs and to design new active inhibitors. This novel series of 2,2'-bithienyl derivatives gives new insights into the design of AANAT inhibitors.
authors.affiliation: Centre d'Etudes et de Recherche sur le Medicament de Normandie, UPRES EA 4258, INC3M FR CNRS 3038, Universite de Caen-Basse Normandie, UFR des Sciences Pharmaceutiques, Boulevard Becquerel, Caen Cedex, France. alban.lepailleur@unicaen.fr
authors.forename: Alban
authors.initials: A
authors.lastname: Lepailleur
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lemaître
authors.forename: Xiao
authors.initials: X
authors.lastname: Feng
authors.forename: Jana
authors.initials: J
authors.lastname: Sopkova-de Oliveira Santos
authors.forename: Philippe
authors.initials: P
authors.lastname: Delagrange
authors.forename: Jean
authors.initials: J
authors.lastname: Boutin
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
authors.forename: Ronan
authors.initials: R
authors.lastname: Bureau
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
mesh_terms: D000818:Animals; D047068:Arylalkylamine N-Acetyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D012756:Sheep; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D013876:Thiophenes; D047068:Arylalkylamine N-Acetyltransferase