MDPath: Unraveling Allosteric Communication Paths of Drug Targets through Molecular Dynamics Simulations

Abstract

Understanding allosteric communication in proteins remains a critical challenge for structure-based, rational drug design. We present MDPath, a Python toolkit for analyzing allosteric communication paths in molecular dynamics simulations using NMI-based analysis. We demonstrate MDPath’s ability to identify both established and novel GPCR allosteric mechanisms using the β2-adrenoceptor, adenosine A2A receptor, and μ-opioid receptor as model systems. The toolkit reveals ligand-specific allosteric effects in β2-adrenoceptor and MOR, illustrating how protein–ligand interactions drive conformational changes. Analysis of ABL1 kinase in complex with allosteric and orthosteric inhibitors demonstrates the broader applicability of the approach. Ultimately, MDPath provides an open-source framework for mapping allosteric communication within proteins, advancing structure-based drug design (https://github.com/wolberlab/mdpath).