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.

Pedro Cruz-Vicente,Samuel Silvestre,Luís A Passarinha,Ana M Gonçalves,Octávio Ferreira,João A Queiroz,Eugenia Gallardo

doi:10.3390/ph15010051

Pedro Cruz-Vicente, Samuel Silvestre + Show 5 more

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https://doi.org/10.3390/ph15010051

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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.

Highlights

With the increasing life expectancy of the population, neurodegenerative disorders (ND) such as Alzheimer’s and Parkinson’s disease (PD), are becoming more common and recognized as a social problem to modern societies [1]
Taking into account the results described in the present work and despite the inhibition levels observed in our assays and the need for more studies, especially at the in-vitro and in-vivo levels, we consider that these compounds may have potential interest in the context of PD and can be new skeletons for further exploration in the medicinal chemistry of COMT inhibitors
A set of molecules with potential interest in PD acting as COMT inhibitors was discovered through a computational-based approach

Summary

Introduction

With the increasing life expectancy of the population, neurodegenerative disorders (ND) such as Alzheimer’s and Parkinson’s disease (PD), are becoming more common and recognized as a social problem to modern societies [1]. Pharmaceuticals 2022, 15, 51 relief, mainly aiming to restore dopaminergic function [2] This strategy is not capable of stopping the progression of the disease and the advance of neurodegeneration and symptom aggravation [2]. The most effective drug combination used in PD treatment is levodopa (L-DOPA) combined with aromatic L-amino acid decarboxylase and catechol-O-methyltransferase (COMT) inhibitors to restore dopaminergic brain levels [2]. Their long-term administration is generally associated with harmful side effects that affect the patient’s quality of life, and a loss in pharmacological effect is usually observed over time [3]. This enzyme appears as two distinct isoforms, a soluble isoform (SCOMT) mainly expressed in the peripheric systems, such as the liver, kidney, and intestines, and a membrane-bound (MBCOMT)

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