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. [excerpt]