SHOP: a method for structure-based fragment and scaffold hopping
| Autor: | Guillem Plasencia, Ismael Zamora, Manuel Pastor, Fabien Fontaine, Simon Cross |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Pharmacology
Scaffold Virtual screening Molecular Structure Computer science Drug discovery Organic Chemistry Computational Biology Proteins Computational biology Scaffold hopping Grid Ligands Biochemistry Combinatorial chemistry Ranking (information retrieval) Fragment (logic) Drug Discovery Molecular Medicine Structure based Humans General Pharmacology Toxicology and Pharmaceutics Algorithms Software Protein Binding |
| Zdroj: | ChemMedChem. 4(3) |
| ISSN: | 1860-7187 |
| Popis: | A new method for fragment and scaffold replacement is presented that generates new families of compounds with biological activity, using GRID molecular interaction fields (MIFs) and the crystal structure of the targets. In contrast to virtual screening strategies, this methodology aims only to replace a fragment of the original molecule, maintaining the other structural elements that are known or suspected to have a critical role in ligand binding. First, we report a validation of the method, recovering up to 95% of the original fragments searched among the top-five proposed solutions, using 164 fragment queries from 11 diverse targets. Second, six key customizable parameters are investigated, concluding that filtering the receptor MIF using the co-crystallized ligand atom type has the greatest impact on the ranking of the proposed solutions. Finally, 11 examples using more realistic scenarios have been performed; diverse chemotypes are returned, including some that are similar to compounds that are known to bind to similar targets. |
| Databáze: | OpenAIRE |
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