Hit-to-Lead Medicinal Chemistry

Hit-to-Lead medicinal chemistry is the process through which “hits” are converted into “leads.” Fundamental to the process is to gain confidence, first that a hit compound can be developed into a robust (lead) series, and second that the leads have the potential to be converted into drug candidates. Such confidence is gained in a stepwise fashion: initially, hit compounds must have their activity confirmed, and second it must be demonstrated that structural modification of the hit can result in changes in biological activity, thus generating a series. Third, members of the series must pass a series of so-called “developability filters,” thus ensuring that there is a high chance of success in the subsequent phase of lead optimization. The hit-to-lead phase is highly important, as chemists are frequently presented with multiple hits from which to identify a small number of series to take forward. Selection at this point will have a direct impact on the success of lead optimization. Keywords: hit; lead; lead optimization; fragment; ligand efficiency