|
|
| The View From Here Hit-to-lead approaches The main source of hits continues to be HTS. Screening is followed by two distinct phases: hit validation and hit optimization. Increasingly, a knowledge-based approach to hit validation is being adopted. Checklists of desired and undesired attributes of hits are often compiled; centred around potency, selectivity, physicochemical and ADMET properties, ease of synthesis, novelty, and SAR. In recent years, the emphasis on physicochemical properties has led to the concept of ligand efficiency and increased interest in fragment-based drug discovery. To generate early SAR, readily available analogs of hits can be retrieved using substructure and similarity searching. Hits that are amenable to parallel synthesis of libraries are often prioritized and the skills for making libraries are well developed among hit-to-lead chemists. When the hit-to-lead process was first introduced the emphasis was on increasing potency. Today, multiple parameters are optimized in parallel to produce leads with a balanced profile of biological and physicochemical properties. It is advantageous to have multiple series in hit optimization so that more than one series is available for lead optimization. The universal use of hit-to-lead programmes makes this topic interesting reading in this issue of Drug Discovery Today E-Choice. Enjoy the read! Richard Morphy |
Many pharmaceutical companies have introduced a distinctive ‘hit-to-lead’ stage to drug discovery programmes. A common goal of hit-to-lead projects is to build confidence in a chemical series, reducing the risk that the commitment of additional resources in lead optimization will be in vain. Indeed, the importance of the hit-to-lead stage to the overall drug discovery process cannot be overstated. The decisions made at this early time point, in terms of which hits to progress, fundamentally influence the chance of an NCE progressing successfully to market.