Editorial: Structure-Based Drug Design for Diagnosis and Treatment of Neurological Diseases

Abstract

Written by researchers brought together by COST Action CM1103 to address multi-target drug design for the complex challenge of neuropathology, the interdisciplinary reviews span the range from computational enzymology through medicinal chemistry and pharmacology to human studies.To introduce the process of designing drugs that hit the multiple targets identified as important complex neuropathologies, Hughes et al. present a brief overview of the current approaches of approaches of data-mining, in silico screening, and rational drug design that rely heavily on clinical and biological validation of suitable targets and the molecular understanding of these targets by their crystallographic structures. Computational advances have been particularly important in the last 5 years, tackling the workload required for multiple targets. Nikolic et al. used data-mining to search for off-target activities, followed by docking compounds to targets to assess their potential as ligands, to provide new leads for experimental confirmation and optimization. Through cheminformatic, 3D-QSAR and virtual screening methodologies, ligands were identified for the traditional neurotransmitter breakdown enzymes, cholinesterases and monoamine oxidases, that also bind to combinations of dopamine, serotonin and histamine receptors, a vital contribution to efficiency in the rational design of multipotent ligands with selected polypharmacology. The next article moves into molecular dynamics on receptors where ligand binding can increase or decrease the response of the receptor, and on to ion channels and their conformational changes responsible for gating. Vianello et al. also review the investigations on the critical chemical step in the inactivation of monoamine oxidase B by selegiline, using a combination of the high-resolution quantum mechanical calculations with molecular mechanics (multiscale QM/MM simulation). Reviewing a hotly-debated topic, the article gives a clear exposition of the evidence for a hydride mechanism for monoamine oxidases.Although computational methods have accelerated compound discovery, lead compounds must still be synthesized. Marco-Contelles et al. describe the optimization of a compound designed to inhibit multiple targets in Alzheimer's disease, showing the derivation of ASS234 from single-target ligands and its assessment, including inhibition of cholinesterases and monoamine oxidases, antioxidant properties, low toxicity and suitable permeability. In vivo, ASS234 proved to be neuroprotective and to prevent β-amyloid aggregation in a mouse model. The medicinal chemistry theme continues with two articles on drug design for receptors. Khanfar et al. focus on combinations with antagonists of the histamine H3 receptor. H3R plays an important role as a hetero-receptor in the modulation of the release of other neurotransmitters including

Polypharmacology of Berberine Based on Multi-Target Binding Motifs

“…The strategy relies on the knowledge of three-dimensional structures of biological targets, which is characterized as structure-based drug design (SBDD). During the past few decades, there has been a steep rise in the computer-aided drug design (CADD) that can assist in carrying out the process of SBDD from the selection of a target to the generation and evaluation of lead compounds effectively ( Ramsay and Di Giovanni, 2017 ). Meanwhile, the explosion of structural information has provided exciting opportunities for SBDD ( Réau et al, 2018 ).…”

Efficacy of a Novel Nanohydrogel Formulation Containing Dopamine, Chitosan Nanoparticles, and Tridax procumbens Extract for Enhanced Wound Healing in Human Gingival Fibroblast Cells: An In Vitro Study

“…It has also been shown to be susceptible to oxidation, which often hinders its effectiveness in reaching the desired target site. To address this challenge, combining dopamine with a nanoparticle, a cationic polysaccharide chitosan nanohydrogel proved advantageous [12][13][14][15]. Combining chitosan-based nanoparticles with dopamine led to increased cell proliferation and improved wound healing.…”

Phase separation and pathologic transitions of RNP condensates in neurons: implications for amyotrophic lateral sclerosis, frontotemporal dementia and other neurodegenerative disorders

“…Arvinas Biopharmaceuticals, Pfizer, and Genentech have all investigated the application of PROTACs in neurodegenerative diseases, particularly in targeting pathological proteins such as tau and α-synuclein in AD and PD. Pioneering research in the use of PROTACs for AD demonstrated the activity of TH006 against the elimination of Tau by recruiting von Hippel-Lindau (VHL) E3 ligase (Ramsay and Di Giovanni, 2017). Since then, different groups have developed Tau-Keap1-CPP, QC-01-175, and C004019 PROTACs employing Keap1, CRBN, and VHL E3 ligases, respectively, for the targeted degradation of Tau in AD models (Cummings, 2021;Karlawish and Grill, 2021;Wang et al, 2021).…”