title: Pharmacophore-Based 3D-QSAR Analysis of Thienyl Chalcones as a New Class of Human MAO-B Inhibitors: Investigation of Combined Quantum Chemical and Molecular Dynamics Approach.
abstract: Selective monoamine oxidase-B (MAO-B) inhibitors are imperative in the treatment of various neurodegenerative disorders. Herein, we describe the pharmacophore generation and atom-based three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses of previously reported thiophene-based hMAO-B inhibitors by our research group. The aim of this study was to identify the principal structural features that could potentially be responsible for the inhibitory activity of hMAO-B inhibitors. The best pharmacophore model generated was the four-point assay of AHRR.8. The pharmacophore model exhibited good correlation with its predictability of the statistically valid 3D-QSAR analyses. Density functional theory calculations were further employed on the lead molecule (2E)-1-(5-bromothiophen-2-yl)-3-[4-(dimethylamino) phenyl] prop-2-en-1-one (Tb5) to investigate the electrostatic potential surface and analyze the natural bond orbital toward the binding characteristics. Molecular dynamics simulations were performed to characterize the molecular level interactions and relative energies of the hMAO isoforms: hMAO-A and hMAO-B with three potent and selective hMAO-B inhibitors (Tb5, Tb6, and Tb9). The results of both continuous and accelerated molecular dynamics simulations demonstrate a distinct preference of the three ligands to bind to hMAO-B rather than hMAO-A.
authors.affiliation: Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy , Palakkad 678557, Kerala, India.
authors.forename: Bijo
authors.initials: B
authors.lastname: Mathew
authors.affiliation: School of Health Sciences, University of KwaZulu-Natal , Westville, Durban 4001, South Africa.
authors.forename: Adebayo A
authors.initials: AA
authors.lastname: Adeniyi
authors.affiliation: Department of Pharmaceutical Chemistry, Al Shifa College of Pharmacy , Perinthalmanna 679325, Kerala, India.
authors.forename: Sanal
authors.initials: S
authors.lastname: Dev
authors.affiliation: School of Pure & Applied Physics, M.G. University , Kottayam 686560, India.
authors.forename: Monu
authors.identifier: 0000-0003-1947-9691
authors.initials: M
authors.lastname: Joy
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Hacettepe University , Sıhhiye, Ankara 06100, Turkey.
authors.forename: Gülberk
authors.initials: G
authors.lastname: Ucar
authors.affiliation: Department of Pharmacology, Grace College of Pharmacy , Palakkad 678004, Kerala, India.
authors.forename: Githa Elizabeth
authors.initials: GE
authors.lastname: Mathew
authors.affiliation: School of Health Sciences, University of KwaZulu-Natal , Westville, Durban 4001, South Africa.
authors.forename: Ashona
authors.initials: A
authors.lastname: Singh-Pillay
authors.affiliation: School of Health Sciences, University of KwaZulu-Natal , Westville, Durban 4001, South Africa.
authors.forename: Mahmoud E S
authors.initials: ME
authors.lastname: Soliman
mesh_terms: D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D056004:Molecular Dynamics Simulation; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory
chemical_list: D047188:Chalcones; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase