The importance of discerning shape in molecular pharmacology

Shape is a fundamentally important molecular feature that often determines the fate of a compound in terms of molecular interactions with preferred and non-preferred biological targets. Complementarity of binding in small-molecule–protein, peptide–receptor, antigen–antibody and protein–protein interactions is the key to life and survival and also to targeting molecules with bioactivity. We review the application of shape in various biological systems such as substrate recognition, ligand specificity or selectivity and antibody recognition in the context of computational methods such as docking, quantitative structure–activity relationships, classification models and similarity-search algorithms. These in silico pharmacology methods have recently demonstrated the importance and applicability of determining molecular shape in drug discovery, virtual screening and predictive toxicology. The results from recently published studies show that shape and shape-based descriptors are at least as useful as other traditional molecular descriptors.