期刊
JOURNAL OF COMPUTATIONAL CHEMISTRY
卷 35, 期 29, 页码 2114-2121出版社
WILEY
DOI: 10.1002/jcc.23726
关键词
molecular recognition; structural complexity; library preparation; drug design; druggability; chirality
资金
- Excellence Initiative of the German Federal Government through the Junior Research Group Program [ZUK 43]
- Excellence Initiative of the German State Government through the Junior Research Group Program [ZUK 43]
- Federal State of Baden-Wurttemberg (Ministry of Arts and Science) through the Zukunftsoffensive IV (ZO IV) Juniorprofessoren-Programm
The content of chiral carbon atoms or structural complexity, which is known to correlate well with relevant physicochemical properties of small molecules, represents a promising descriptor that could fill the gap in existing drug discovery between ligand library filtering rules and the corresponding properties of the target's recognition site. Herein, we present an in silico study on the yet unclear underlying correlations between molecular complexity and other more sophisticated physicochemical and biological properties. By analyzing thousands of protein-ligand complexes from DrugBank, we show that increasing molecular complexity of drugs is an approach to addressing particularly lowdruggability and polar recognition sites. We also show that biologically relevant protein classes characteristically bind molecules with a certain degree of structural complexity. Three distinct behaviors toward drug recognition are described. The reported results set the basis for a better understanding of protein-drug recognition, and open the possibility of including target information in the filtering of large ligand libraries for screening. (c) 2014 Wiley Periodicals, Inc.
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