Following the Rabbit into Chemical Space

Structure-based drug-discovery often begins with screens of compound libraries, using molecular docking. Recently, these libraries have expanded from three million “in-stock” to over seven billion diverse, stereogenic, and readily available molecules. These “tangible” molecules have not previously been synthesized, and are not synthesized until they are priorized, typically computationally. In the last four years, campaigns against the multiple receptors have found novel chemotypes with high potencies directly out of docking screens. I will discuss a recent application to the discovery of new ligands to control calcium hemostasis via the calcium sensing receptor. Methods questions will also be considered: how docking score, hit rate, and affinity improve as the libraries grow, how number tested affects the quality of the experimental actives, and whether there is continued advantage in further growing the libraries.