Unveiling Dynamic Hotspots in Protein–Ligand Binding: Accelerating Target and Drug Discovery Approaches

Computational methods have transformed target and drug discovery, significantly accelerating the identification of biological targets and lead compounds. Despite its limitations, in silico molecular docking represents a foundational tool. Molecular Dynamics (MD) simulations, employing accurate force fields, provide near-realistic insights into a compound's behavior within a biological target. However, docking and MD predictions may be unreliable without precise knowledge of the target binding site. Through MD simulations, we investigated 100 co-crystal structures of biological targets complexed with active compounds, identifying key structural and energy dynamic features that govern target-ligand interactions. Our analysis provides a detailed quantitative description of these parameters, offering critical validation for improving the predictive reliability of docking and MD simulations. This work provides a robust framework for refining early-stage drug discovery and target identification.