Tagged fragment method for evolutionary structure-based de novo lead generation and optimization |
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Authors: | Liu Qian Masek Brian Smith Karl Smith Julian |
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Institution: | Tripos, Inc., 1699 South Hanley Road, St. Louis, Missouri 63144, USA. qliu@tripos.com |
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Abstract: | 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. |
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