Is the Functional Response of a Receptor Determined by the Thermodynamics of Ligand Binding?Click to copy article linkArticle link copied!
- Martin VögeleMartin VögeleSchrödinger, Inc., 1540 Broadway 24th Floor, New York, New York 10036, United StatesMore by Martin Vögele
- Bin W. ZhangBin W. ZhangSchrödinger, Inc., 1540 Broadway 24th Floor, New York, New York 10036, United StatesMore by Bin W. Zhang
- Jonas Kaindl
- Lingle Wang*Lingle Wang*Email: [email protected]. Phone: +1 (212) 548-2381.Schrödinger, Inc., 1540 Broadway 24th Floor, New York, New York 10036, United StatesMore by Lingle Wang
Abstract

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.
Cited By
Smart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by ACS Publications if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
This article is cited by 10 publications.
- 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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.
Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.
The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.