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Expanding the Conformational Selection Paradigm in Protein-Ligand Docking

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Computational Drug Discovery and Design

Part of the book series: Methods in Molecular Biology ((MIMB,volume 819))

Abstract

Conformational selection emerges as a theme in macromolecular interactions. Data validate it as a prevailing mechanism in protein–protein, protein–DNA, protein–RNA, and protein–small molecule drug recognition. This raises the question of whether this fundamental biomolecular binding mechanism can be used to improve drug docking and discovery. Actually, in practice this has already been taking place for some years in increasing numbers. Essentially, it argues for using not a single conformer, but an ensemble. The paradigm of conformational selection holds that because the ensemble is heterogeneous, within it there will be states whose conformation matches that of the ligand. Even if the population of this state is low, since it is favorable for binding the ligand, it will bind to it with a subsequent population shift toward this conformer. Here we suggest expanding it by first modeling all protein interactions in the cell by using Prism, an efficient motif-based protein–protein interaction modeling strategy, followed by ensemble generation. Such a strategy could be particularly useful for signaling proteins, which are major targets in drug discovery and bind multiple partners through a shared binding site, each with some—minor or major—conformational change.

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Acknowledgments

This work has been supported by TUBITAK (Research Grant Numbers: 109T343 and 109E207). Guray Kuzu is supported by a TUBITAK fellowship. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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Authors and Affiliations

  1. Center for Computational Biology and Bioinformatics and College of Engineering, Koc University Rumelifeneri Yolu, Istanbul, Turkey

    Guray Kuzu, Ozlem Keskin & Attila Gursoy

  2. Center for Cancer Research Nanobiology Program, National Cancer Institute, Frederick, MD, USA

    Ruth Nussinov

  3. Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ruth Nussinov

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  1. Guray Kuzu
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  2. Ozlem Keskin
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  3. Attila Gursoy
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  4. Ruth Nussinov
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Correspondence to Ruth Nussinov .

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Editors and Affiliations

  1. University of Utah, 30 South 2000 East Rm 307, Salt Lake City, 84112-5820, California, USA

    Riccardo Baron

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Kuzu, G., Keskin, O., Gursoy, A., Nussinov, R. (2012). Expanding the Conformational Selection Paradigm in Protein-Ligand Docking. In: Baron, R. (eds) Computational Drug Discovery and Design. Methods in Molecular Biology, vol 819. Springer, New York, NY. https://doi.org/10.1007/978-1-61779-465-0_5

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  • DOI: https://doi.org/10.1007/978-1-61779-465-0_5

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