Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

Abstract

Neurodegenerative diseases (ND), including Alzheimer’s (AD) and Parkinson’s Disease (PD), are becoming increasingly more common and are recognized as a social problem in modern societies. These disorders are characterized by a progressive neurodegeneration and are considered one of the main causes of disability and mortality worldwide. Currently, there is no existing cure for AD nor PD and the clinically used drugs aim only at symptomatic relief, and are not capable of stopping neurodegeneration. Over the last years, several drug candidates reached clinical trials phases, but they were suspended, mainly because of the unsatisfactory pharmacological benefits. Recently, the number of compounds developed using in silico approaches has been increasing at a promising rate, mainly evaluating the affinity for several macromolecular targets and applying filters to exclude compounds with potentially unfavorable pharmacokinetics. Thus, in this review, an overview of the current therapeutics in use for these two ND, the main targets in drug development, and the primary studies published in the last five years that used in silico approaches to design novel drug candidates for AD and PD treatment will be presented. In addition, future perspectives for the treatment of these ND will also be briefly discussed.

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

“…From an initial set of 100 molecules with known COMT inhibitory properties, the 18 most promising compounds were selected to integrate into the study training set (Figure 1) [9]. This selection was carried out based on the compounds' structure and existing in-silico data regarding their interaction with COMT, including molecular docking and molecular dynamics interactions with the protein active site [29] and the ADMET (absorption, distribution, metabolism, excretion, and toxicity) property prevision, as well as their in-vitro and in-vivo COMT inhibitory potency and bioavailability [9]. The 18 selected most promising compounds, used as the training set, were drawn in ChemDraw (v. 12.0), and their conformational energies were minimized using the MM2 force field in Chem3D (v. 12.0) to improve the reliability of the obtained results.…”

“…The binding poses were generated using the Lamarckian genetic computational algorithm. The hits were ranked based on their binding energies and their binding free energy (∆G), expressed in kcal/mol by the software, and their atomic interactions were further studied using the PMV (v. 1.5.6) tool and the Discovery Studios (v. 4.5) program to better visualize and identify the most important atomic interactions [29].…”

In Silico Approaches: A Way to Unveil Novel Therapeutic Drugs for Cervical Cancer Management

“…Molecular dynamics techniques entail the motion principles to molecules and are frequently used to perform binding mode studies and to predict the stability of a ligand–target complex, giving a deeper understanding to the researchers on the interaction of a ligand to a biomolecular target [ 9 , 11 , 12 , 13 ]. On the other hand, ligand-based methods, including similarity searching, pharmacophore modeling, and quantitative structure–activity relationship (QSAR) studies, use the information of groups of small molecules with different structures capable of interacting with the target to identify new and powerful compounds [ 12 , 14 ]. These methods are usually applied when the 3D structure of the target is not available and assume that analogous compounds show similar biological activity and interaction with the target.…”

Assessing REM Sleep Behaviour Disorder: From Machine Learning Classification to the Definition of a Continuous Dissociation Index

“…Even though a causal therapy for these diseases does not currently exist, emerging evidence points out that life style modification can dramatically slow down the disease progression [ 3 , 4 ]. Moreover, new neuro-protective drugs are under study [ 5 ], which will be likely effective only if administered in very early, pre-clinical stages of the pathology [ 6 ]. This points out the need for early markers of neurodegeneration.…”