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Is the Functional Response of a Receptor Determined by the Thermodynamics of Ligand Binding?
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    Is the Functional Response of a Receptor Determined by the Thermodynamics of Ligand Binding?
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    Journal of Chemical Theory and Computation

    Cite this: J. Chem. Theory Comput. 2023, 19, 22, 8414–8422
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    https://doi.org/10.1021/acs.jctc.3c00899
    Published November 9, 2023
    Copyright © 2023 American Chemical Society

    Abstract

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    For an effective drug, strong binding to the target protein is a prerequisite, but it is not enough. To produce a particular functional response, drugs need to either block the proteins’ functions or modulate their activities by changing their conformational equilibrium. The binding free energy of a compound to its target is routinely calculated, but the timescales for the protein conformational changes are prohibitively long to be efficiently modeled via physics-based simulations. Thermodynamic principles suggest that the binding free energies of the ligands with different receptor conformations may infer their efficacy. However, this hypothesis has not been thoroughly validated. We present an actionable protocol and a comprehensive study to show that binding thermodynamics provides a strong predictor of the efficacy of a ligand. We apply the absolute binding free energy perturbation method to ligands bound to active and inactive states of eight G protein-coupled receptors and a nuclear receptor and then compare the resulting binding free energies. We find that carefully designed restraints are often necessary to efficiently model the corresponding conformational ensembles for each state. Our method achieves unprecedented performance in classifying ligands as agonists or antagonists across the various investigated receptors, all of which are important drug targets.

    Copyright © 2023 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jctc.3c00899.

    • Additional details on simulation setup and data analysis, including tables of results from all free energy calculations (PDF)

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    This article is cited by 10 publications.

    1. David A. Cooper, Joseph DePaolo-Boisvert, Stanley A. Nicholson, Barien Gad, David D. L. Minh. Intracellular Pocket Conformations Determine Signaling Efficacy through the μ Opioid Receptor. Journal of Chemical Information and Modeling 2025, Article ASAP.
    2. Bin W. Zhang, Mikolai Fajer, Wei Chen, Francesca Moraca, Lingle Wang. Leveraging the Thermodynamics of Protein Conformations in Drug Discovery. Journal of Chemical Information and Modeling 2025, 65 (1) , 252-264. https://doi.org/10.1021/acs.jcim.4c01612
    3. Gabriel T. Galdino, Olivier Mailhot, Rafael Najmanovich. Understanding and Predicting Ligand Efficacy in the μ-Opioid Receptor through Quantitative Dynamical Analysis of Complex Structures. Journal of Chemical Information and Modeling 2024, 64 (22) , 8549-8561. https://doi.org/10.1021/acs.jcim.4c00788
    4. Runtong Qian, Jing Xue, You Xu, Jing Huang. Alchemical Transformations and Beyond: Recent Advances and Real-World Applications of Free Energy Calculations in Drug Discovery. Journal of Chemical Information and Modeling 2024, 64 (19) , 7214-7237. https://doi.org/10.1021/acs.jcim.4c01024
    5. Finlay Clark, Graeme R. Robb, Daniel J. Cole, Julien Michel. Automated Adaptive Absolute Binding Free Energy Calculations. Journal of Chemical Theory and Computation 2024, 20 (18) , 7806-7828. https://doi.org/10.1021/acs.jctc.4c00806
    6. Linfeng Hu, Ke An, Yue Zhang, Chen Bai. Exploring the Activation Mechanism of the GPR183 Receptor. The Journal of Physical Chemistry B 2024, 128 (25) , 6071-6081. https://doi.org/10.1021/acs.jpcb.4c02812
    7. Paolo Conflitti, Edward Lyman, Mark S. P. Sansom, Peter W. Hildebrand, Hugo Gutiérrez-de-Terán, Paolo Carloni, T. Bertie Ansell, Shuguang Yuan, Patrick Barth, Anne S. Robinson, Christopher G. Tate, David Gloriam, Stephan Grzesiek, Matthew T. Eddy, Scott Prosser, Vittorio Limongelli. Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery. Nature Reviews Drug Discovery 2025, 409 https://doi.org/10.1038/s41573-024-01083-3
    8. Sutong Xiang, Zhe Wang, Qirui Deng, Rongfan Tang, Qinghua Wang, Yang Yu, Tingjun Hou, Haiping Hao, Huiyong Sun. Shared interaction pathways of ligands targeting the ligand-binding pocket of nuclear receptors. Cell Reports Physical Science 2025, 6 (1) , 102352. https://doi.org/10.1016/j.xcrp.2024.102352
    9. Joan Gizzio, Abhishek Thakur, Allan Haldane, Carol Beth Post, Ronald M. Levy. Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases. Nature Communications 2024, 15 (1) https://doi.org/10.1038/s41467-024-50812-0
    10. David A. Cooper, Joseph DePaolo-Boisvert, Stanley A. Nicholson, Barien Gad, David D. L. Minh. Intracellular pocket conformations determine signaling efficacy through the μ opioid receptor. 2024https://doi.org/10.1101/2024.04.03.588021
    11. Milan Sencanski, Sanja Glisic, Valentina Kubale, Marko Cotman, Janez Mavri, Milka Vrecl. Computational Modeling and Characterization of Peptides Derived from Nanobody Complementary-Determining Region 2 (CDR2) Targeting Active-State Conformation of the β2-Adrenergic Receptor (β2AR). Biomolecules 2024, 14 (4) , 423. https://doi.org/10.3390/biom14040423

    Journal of Chemical Theory and Computation

    Cite this: J. Chem. Theory Comput. 2023, 19, 22, 8414–8422
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jctc.3c00899
    Published November 9, 2023
    Copyright © 2023 American Chemical Society

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