Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson’s Disease: Pharmacophore Modeling, Molecular Docking and In Vitro Experimental Validation Studies

Abstract

A pharmacophore-based virtual screening methodology was used to discover new catecholO-methyltransferase (COMT) inhibitors with interest in Parkinson’s disease therapy. To do so, pharmacophore models were constructed using the structure of known inhibitors and then they were used in a screening in the ZINCPharmer database to discover hit molecules with the desired structural moieties and drug-likeness properties. Following this, the 50 best ranked molecules were submitted to molecular docking to better understand their atomic interactions and binding poses with the COMT (PDB#6I3C) active site. Additionally, the hits’ ADMET properties were also studied to improve the obtained results and to select the most promising compounds to advance for in-vitro studies. Then, the 10 compounds selected were purchased and studied regarding their in-vitro inhibitory potency on human recombinant membrane-bound COMT (MBCOMT), as well as their cytotoxicity in rat dopaminergic cells (N27) and human dermal fibroblasts (NHDF). Of these, the compound ZIN27985035 displayed the best results: For MBCOMT inhibition an IC50 of 17.6 nM was determined, and low cytotoxicity was observed in both cell lines (61.26 and 40.32 µM, respectively). Therefore, the promising results obtained, combined with the structure similarity with commercial COMT inhibitors, can allow for the future development of a potential new Parkinson’s disease drug candidate with improved properties. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.