Molecular Dynamics Simulations Reveal Fundamental Role of Water As Factor Determining Affinity of Binding of β-Blocker Nebivolol to β₂-Adrenergic Receptor

The β-adrenergic antagonists (β-blockers) constitute a class of drugs that have well-established roles in treatments of various cardiovascular diseases. Despite a 50 year history, there are two clinically important subtypes of β-adrenergic receptors (βARs) called β1AR and β2AR that still are promising drug targets. Our study maps the interactions between nebivolol―one of the most efficient β-blocking agents―and the β2-adrenergic receptor by simulating two optical isomers of nebivolol: ssss-nebivolol and srrr-nebivolol. The srrr-configuration binds preferentially to β1AR and β2AR. The ssss-form has much lower binding affinity to both of them. Our work indicates that water is a very important component of the binding site of the β2AR receptor. We found that the higher stereoselectivity of the srrr-configuration is due to interactions with water molecules, which extensively hydrate the binding site of β2AR. By lowering the energy of binding, water enhanced the affinity of the srrr-form to β2AR. We also address the problem of β1AR/β2AR selectivity. At higher concentrations, all β-blocking agents lose their specificity and bind nonselectively, causing many adverse effects. Our simulations indicate that PHE194, TYR308, and ILE309 of the β2AR and the corresponding residues of the β1AR receptor may be important determinants of β1AR versus β2AR selectivity.β-肾上腺素能拮抗剂（β-adrenergic antagonists，即β受体阻滞剂β-blockers）是一类已被广泛证实可用于多种心血管疾病治疗的药物。尽管该类药物的研究与应用已有五十年历史，目前临床上仍有两种重要的β肾上腺素能受体（β-adrenergic receptors, βARs）亚型——β1AR与β2AR——仍是极具开发价值的药物靶点。本研究通过模拟奈必洛尔（nebivolol）的两种光学异构体：ssss-奈必洛尔与srrr-奈必洛尔，解析了奈必洛尔——目前最为高效的β受体阻滞剂之一——与β2肾上腺素能受体的相互作用机制。其中srrr构型对β1AR与β2AR均具有优先结合能力，而ssss构型与二者的结合亲和力均显著较低。本研究发现水分子是β2AR结合位点的关键组成部分，进一步揭示srrr构型更高的立体选择性源于其与水分子的相互作用：β2AR的结合位点被水分子广泛水合，通过降低结合自由能，提升了srrr构型与β2AR的结合亲和力。本研究还探讨了β1AR与β2AR的选择性问题：在高浓度条件下，所有β受体阻滞剂都会丧失特异性，产生非特异性结合并引发多种不良反应。模拟结果显示，β2AR的PHE194、TYR308与ILE309残基，以及β1AR的对应残基，可能是决定β1AR与β2AR选择性的关键因素。