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

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.