Structural conservation of druggable Hot spots in protein - Protein interfaces

Kozakov D.; Hall D.R.; Chuang G.-Y.Cencic R.Brenke R.Grove L.E.Beglov D.Pelletier J.Whitty A.Vajda S.

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Structural conservation of druggable Hot spots in protein - Protein interfaces

机译：Structural conservation of druggable Hot spots in protein - Protein interfaces

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Despite the growing number of examples of small-molecule inhibitors that disrupt protein - protein interactions (PPIs), the origin of druggability of such targets is poorly understood. To identify druggable sites in protein - protein interfaces we combine computational solvent mapping, which explores the protein surface using a variety of small "probe" molecules, with a conformer generator to account for side-chain flexibility. Applications to unliganded structures of 15 PPI target proteins show that the druggable sites comprise a cluster of binding hot spots, distinguishable from other regions of the protein due to their concave topology combined with a pattern of hydrophobic and polar functionality. This combination of properties confers on the hot spots a tendency to bind organic species possessing some polar groups decorating largely hydrophobic scaffolds. Thus, druggable sites at PPI are not simply sites that are complementary to particular organic functionality, but rather possess a general tendency to bind organic compounds with a variety of structures, including key side chains of the partner protein. Results also highlight the importance of conformational adaptivity at the binding site to allow the hot spots to expand to accommodate a ligand of drug-like dimensions. The critical components of this adaptivity are largely local, involving primarily low energy side-chain motions within 6 ? of a hot spot. The structural and physicochemical signature of druggable sites at PPI interfaces is sufficiently robust to be detectable from the structure of the unliganded protein, even when substantial conformational adaptation is required for optimal ligand binding.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2011年第33期|13528-13533|共6页
作者
Kozakov D.; Hall D.R.; Chuang G.-Y.Cencic R.Brenke R.Grove L.E.Beglov D.Pelletier J.Whitty A.Vajda S.;
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作者单位

Department of Chemistry, Boston University, Boston, MA 02215, United States;

Department of Biomedical Engineering, Boston University, Boston, MA 02215, United States;

Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, CanadaWentworth Institute of Technology, Boston, MA 02115, United States;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Fragment-based drug discovery; Inhibitor design; Ligand binding site; Side-chain adjustment;

Structural conservation of druggable Hot spots in protein - Protein interfaces

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