Tagged Fragment Method for Evolutionary Structure-Based De Novo Lead Generation and Optimization
Qian Liu, Brian B. Masek, Karl M. Smith, J. E. Smith · Journal of Medicinal Chemistry · 2007
Here we describe a computer-assisted de novo drug design method, EAISFD, which combines the de novo design engine EA-Inventor with a scoring function featuring the molecular docking program Surflex-Dock. This method employs tagged fragments, which are preserved substructures in EA-Inventor used for base fragment matching in Surflex-Dock, for constructing ligand structures under specific binding motifs. In addition, a target score mechanism is adopted that allows EAISFD to deliver a diverse set of desired structures. This method can be used to design novel ligand scaffolds (lead generation) or to optimize attachments on a fixed scaffold (lead optimization). EAISFD has successfully suggested many known inhibitor scaffolds as well as a number of new scaffold types when applied to p38 MAP kinase.