Schmidt Lisa, de Groot Bert L
Max Planck Institute for Multidisciplinary Sciences, Department of Theoretical and Computational Biophysics, Group of Computational Biomolecular Dynamics Goettingen Germany
Chem Sci. 2025 Apr 22. doi: 10.1039/d4sc04723k.
G protein coupled receptors, particularly class A GPCRs are arguably the most important class of membrane receptors and preferred targets for drug development. Despite extensive research on how ligands modulate the receptor response, discovering new, highly specific ligands remains challenging. However, finding residues outside the conserved microswitches that affect the active-inactive state equilibrium and are specific for a certain receptor, can be beneficial for the design of ligands with higher receptor selectivity. Focusing on the human dopamine receptor 2 (DRD2), we uncover crucial residues for the activation modulation using alchemical non-equilibrium free energy calculations. Our findings match with literature on activation microswitches and experimental studies, while also uncovering novel important residues. Further, we analyzed mutation-induced changes in residue contact networks and found that modulating these networks can lead to a stabilization of the respective opposite state, an effect that could as well be achieved by well-engineered (small) ligands. This way we provide insights into the mechanism of action of the well-known drugs risperidone and bromocriptine and showcase on these two examples how our data can be used for the design of new ligands.
G蛋白偶联受体，尤其是A类GPCR，可谓是最重要的一类膜受体，也是药物研发的首选靶点。尽管对配体如何调节受体反应进行了广泛研究，但发现新的、高度特异性的配体仍然具有挑战性。然而，找到保守微开关之外影响活性-非活性状态平衡且对特定受体具有特异性的残基，可能有助于设计具有更高受体选择性的配体。以人类多巴胺受体2（DRD2）为重点，我们利用炼金术非平衡自由能计算揭示了激活调节的关键残基。我们的发现与关于激活微开关的文献和实验研究相匹配，同时还揭示了新的重要残基。此外，我们分析了突变引起的残基接触网络变化，发现调节这些网络可导致相应相反状态的稳定，这种效果也可通过精心设计的（小）配体实现。通过这种方式，我们深入了解了知名药物利培酮和溴隐亭的作用机制，并以这两个例子展示了如何利用我们的数据设计新的配体。
