Auto In Silico Ligand Directing Evolution to Facilitate the Rapid and Efficient Discovery of Drug Lead.

Motivated by the growing demand for reducing the chemical optimization burden of H2L, we developed auto in silico ligand directing evolution (AILDE, http://chemyang.ccnu.edu.cn/ccb/server/AILDE), an efficient and general approach for the rapid identification of drug leads in accessible chemical space. This computational strategy relies on minor chemical modifications on the scaffold of a hit compound, and it is primarily intended for identifying new lead compounds with minimal losses or, in some cases, even increases in ligand efficiency. We also described how AILDE greatly reduces the chemical optimization burden in the design of mesenchymal-epithelial transition factor (c-Met) kinase inhibitors. We only synthesized eight compounds and found highly efficient compound 5g, which showed an ∼1,000-fold improvement in in vitro activity compared with the hit compound. 5g also displayed excellent in vivo antitumor efficacy as a drug lead. We believe that AILDE may be applied to a large number of studies for rapid design and identification of drug leads.