Fragment-Based Drug Discovery

摘要

The pharmaceutical industry's ability to produce new medicines is directly tied to its success in identifying druglike molecules that target clinically relevant pathways. As a consequence, the research community is constantly seeking to expand and improve its repertoire of lead identification strategies. Most medicinal chemistry leads (i.e., molecules that demonstrate activity in a relevant in vivo model) are evolved from "hits" obtained by screening collections of compounds against functional assays. Chemical optimization strategies can often improve hits' target affinity by 100- to 1000-fold (corresponding to approximately 2.8-4.2 kcal/mol of binding energy) while maintaining their druglike properties. Validated hits are thus typically required to demonstrate functional activity at low-micromolar to high-nanomolar concentrations (corresponding to 6.8-9.5 kcal/mol of binding energy). Since valid hits must possess nearly two-thirds of the net binding energy of fully optimized leads, the industry has traditionally built large collections of highly functionalized compounds in an attempt to identify sufficient numbers of hits.