Drug-Protein Interactions and Mechanisms of Action by Structural Modifications Driving Protein Function

Dear Colleagues,

Currently, the process of development of a drug molecule is characterized by a huge number of failures, due in large part to inadequate pharmacokinetics, lack of efficacy, toxicity, side effects, etc. In the last few decades molecular modelling has been recognized as a powerful tool helping to shed light on structure-activity relationships, by investigating drug–protein interactions at atomic resolution. Moreover, the availability of thousands of three-dimensional structures of protein offers crucial structural information about key macromolecular drug targets.  Starting from drug-target models, the integration of in silico and experimental methods has provided the up-to-date understanding of complex aspects characterizing inter-molecular recognition. For example, flexibility and conformational dynamics of the target is an essential but frequently overlooked aspect in such studies. In fact, receptors may undergo significant local and global structural modifications, following the molecular recognition process, which, subsequently, affects the protein function. Addressing the above-mentioned issues is crucial in evaluating the effect of a binder on the target structure. Computational molecular modelling faces these challenges by employing techniques such as molecular dynamics (MD), which enable quantitative prediction of physical/chemical properties of protein-drug complexes. The emerging enhanced sampling techniques, such as replica exchange MD, metadynamics, simulated annealing and hybrid methods offer improved estimates of the binding free energy by facilitating the system’s escape from conformational traps around local free energy minima. Such computational approaches provide insights into mechanisms of action of drug molecules by exploring both local and non-local effects on protein targets. Hence, they represent a powerful and promising approach aiding in drug discovery and the field of modern medicinal chemistry in general. At present, the research in the area of drug-protein interactions remains an endless source of challenging issues.

This Special Issue will cover latest advances in computational modelling applied to the investigations of physiological and pathological conditions, such as cancer and neurodegenerative diseases. The emphasis will be on: Drug design/screening and molecular docking; classical and enhanced sampling techniques to characterize drug–protein binding, affinity and kinetics; atomistic and coarse-grained approaches to explore local and global effects of drug–protein interactions.

Prof. Dr. Jack A. Tuszynski
Dr. Marco A. Deriu
Guest Editors

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