Biotin's Lessons in Drug Design.

At the heart of drug design is the discovery of molecules that bind with high affinity to their drug targets. Biotin forms the strongest known noncovalent ligand-protein interactions with avidin and streptavidin, achieving femtomolar and picomolar affinities, respectively. This is made even more exceptional because biotin achieves this with a meagre molecular weight of 240 Da. Surprisingly, the approaches by which biotin achieves this are not in the standard repertoire of current medicinal chemistry practice. Biotin's biggest lesson is the importance of nonclassical H-bonds in protein-ligand complexes. Most of biotin's affinity stems from its flexible valeric acid side chain that forms CH-π, CH-O, and classical H-bonds with the lipophilic region of the binding pocket. Biotin also utilizes an oxyanion hole, a sulfur-centered H-bond, and water solvation in the bound state to achieve its potency. The facets and advantages of biotin's approach to binding should be more widely adopted in drug design.