Improving the hit-to-lead process: data-driven assessment of drug-like and lead-like screening hits

We herein outline the usefulness of drug-like screening hits. As for lead-like hits it is of pivotal importance to have a detailed profile with experimental data prior to initiating costly and resource-intense lead optimization programs. Drug-like and lead-like hits derived from HTS campaigns provide good starting points for lead optimization. However, too strong emphasis on potency as hit-selection parameter might hamper the success of such projects. A detailed absorption, distribution, metabolism, excretion and toxicology (ADME–Tox) profiling is needed to help identify hits with a minimum number of (known) liabilities. This is particularly true for drug-like hits. Herein, we describe how to break down large numbers of screening hits and we provide a comprehensive overview of the strengths and weaknesses for each structural class. The overall profile (e.g. ligand efficiency, selectivity and ADME–Tox) is the distinctive feature that will define the priority for follow-up.