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 catechol-O-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.

In Silico Identification of New Anti-SARS-CoV-2 Main Protease (Mpro) Molecules with Pharmacokinetic Properties from Natural Sources Using Molecular Dynamics (MD) Simulations and Hierarchical Virtual Screening

“…*erefore, based on their binding affinities to SARS-CoV-2 M pro , they can be selected as potential drug candidates against SARS-CoV-2 M pro . Several scholars have also used ZINCPHARMER as their preferred pharmacophore-based virtual screening web server while undertaking their respective studies [28,30,[33][34][35].…”

The Catechol O-Methyltransferase Inhibitor Entacapone in the Treatment of Parkinson’s Disease: Personal Reflections on a First-in-Class Drug Development Programme 40 Years On

“…Certainly, preclinical research into COMT inhibition is continuing. At least one compound (ZIN27985035) [27] has emerged as a possible relatively selective inhibitor of MB-COMT, along with a novel chemical series (bicyclic hydropyridines) [29], the implied hope for which is that some of them may replicate or exceed the COMT inhibitory potency of tolcapone, without the associated hepatic toxicity. These and other ideas are, however, all at a very early stage of evaluation and may never be realised as viable pharmaceutical products.…”