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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Pathway and mechanism of drug binding to G-protein-coupled receptors
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Pathway and mechanism of drug binding to G-protein-coupled receptors

机译：药物与G蛋白偶联受体结合的途径和机制

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摘要

How drugs bind to their receptors—from initial association, through drug entry into the binding pocket, to adoption of the final bound conformation, or "pose"—has remained unknown, even for G-protein-coupled receptor modulators, which constitute one-third of all marketed drugs. We captured this pharmaceutically critical process in atomic detail using the first unbiased molecular dynamics simulations in which drug molecules spontaneously associate with G-protein-coupled receptors to achieve final poses matching those determined crystallographically. We found that several beta blockers and a beta agonist all traverse the same well-defined, dominant pathway as they bind to theβ1 - and β2-adre-nergic receptors, initially making contact with a vestibule on each receptor's extracellular surface. Surprisingly, association with this vestibule, at a distance of 15 A from the binding pocket, often presents the largest energetic barrier to binding, despite the fact that subsequent entry into the binding pocket requires the receptor to deform and the drug to squeeze through a narrow passage. The early barrier appears to reflect the substantial dehydration that takes place as the drug associates with the vestibule. Our atomic-level description of the binding process suggests opportunities for allosteric modulation and provides a structural foundation for future optimization of drug-receptor binding and unbinding rates.
机译：药物如何与其受体结合-从最初的结合，到药物进入结合口袋，再到最终结合的构象或“姿势”的采用-甚至对于G蛋白偶联受体调节剂而言，仍然是未知的，在所有上市药品中占三分之一。我们使用第一个无偏分子动力学模拟在原子细节中捕获了这一药学关键过程，在该模拟中，药物分子自发与G蛋白偶联受体缔合，以实现与晶体学确定的那些相匹配的最终姿势。我们发现，几种β受体阻滞剂和β受体激动剂都通过相同的定义明确的显性途径，因为它们与β1-和β2肾上腺素能受体结合，最初与每个受体细胞外表面的前庭接触。出人意料的是，尽管随后进入结合袋需要受体变形并且药物会通过狭窄的空间挤压，但距结合袋15 A的距离与该前庭的结合常常对结合产生最大的能量屏障。通道。早期屏障似乎反映了药物与前庭结合时发生的大量脱水。我们对结合过程的原子级描述提示了变构调节的机会，并为将来优化药物受体结合和解结合速率提供了结构基础。

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