Tagged fragment method for evolutionary structure-based de novo lead generation and optimization.
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.
Liu
Qian
Q
Tripos, Inc., 1699 South Hanley Road, St. Louis, Missouri 63144, USA. qliu@tripos.com
Masek
Brian
B
Smith
Karl
K
Smith
Julian
J
D000465:Algorithms; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008024:Ligands; D015394:Molecular Structure; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D012984:Software; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*
D004791:Enzyme Inhibitors; D008024:Ligands; D048051:p38 Mitogen-Activated Protein Kinases