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Role of protein flexibility in the design of Bcl-XL targeting agents: insight from molecular dynamics

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Abstract

Detailed understanding of protein–ligand interactions is crucial to the design of more effective drugs. This is particularly true when targets are protein interfaces which have flexible, shallow binding sites that exhibit substantial structural rearrangement upon ligand binding. In this study, we use molecular dynamics simulations and free energy calculations to explore the role of ligand-induced conformational changes in modulating the activity of three generations of Bcl-XL inhibitors. We show that the improvement in the binding affinity of each successive ligand design is directly related to a unique and measurable reduction in local flexibility of specific regions of the binding groove, accompanied by the corresponding changes in the secondary structure of the protein. Dynamic analysis of ligand–protein interactions reveals that the latter evolve with each new design consistent with the observed increase in protein stability, and correlate well with the measured binding affinities. Moreover, our free energy calculations predict binding affinities which are in qualitative agreement with experiment, and indicate that hydrogen bonding to Asn100 could play a prominent role in stabilizing the bound conformations of latter generation ligands, which has not been recognized previously. Overall our results suggest that molecular dynamics simulations provide important information on the dynamics of ligand–protein interactions that can be useful in guiding the design of small-molecule inhibitors of protein interfaces.

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Acknowledgments

This work was funded by a grant from Boston College to G.K.

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Authors and Affiliations

  1. Department of Chemistry, Boston College, 2609 Beacon Street, Chestnut Hill, MA, 02135, USA

    William Novak & Goran Krilov

  2. Computational Science, AstraZeneca R&D Boston, 35 Gate House Dr., Waltham, MA, 02451, USA

    Hongming Wang

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  1. William Novak
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  2. Hongming Wang
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  3. Goran Krilov
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Correspondence to Goran Krilov.

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Novak, W., Wang, H. & Krilov, G. Role of protein flexibility in the design of Bcl-XL targeting agents: insight from molecular dynamics. J Comput Aided Mol Des 23, 49–61 (2009). https://doi.org/10.1007/s10822-008-9237-0

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  • DOI: https://doi.org/10.1007/s10822-008-9237-0

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