Smart Integration of Structural Biology and Medicinal Chemistry to Unlock Target‐Driven Drug Discovery

To enhance drug discovery efforts, medicinal chemists should evaluate, filter, and utilize relevant structural information about target proteins. Acquiring and interpreting protein structures is crucial for elucidating ligand-receptor interactions and addressing ADME-related considerations, making it an essential aspect of medicinal chemistry. Proteins exhibit diverse structural organizations, and their conformational variability poses challenges for drug design. Here we draw from our own experience how advances in structural biology have improved medicinal chemists’ access to 3D protein structures and dynamics, while stressing the need for model validation and refinement. To highlight the influence of structural biology on drug discovery, we present case studies. Structural insights into P-glycoprotein have been crucial in addressing multidrug resistance, while the analysis of the oncoprotein β-catenin provides valuable guidance for developing future therapeutic strategies based on innovative technology like targeted protein degradation. Finally, we report about multimeric complexes of proteins (Alsin and AP-4) involved in rare HSPs and the contribution of protein–protein interaction analyses to discover mutation-specific drugs.