Dominant Conformation of Valsartan in Sodium Dodecyl Sulfate Micelle Environment
Dominant Conformation of Valsartan in Sodium Dodecyl Sulfate Micelle Environment
复制标题
十二烷基硫酸钠胶束环境中缬沙坦的主要构象
DOI：
10.1021/jp908958k
复制
发表时间：
2010-03-04
影响因子：
3.3
通讯作者：
Liu, Maili
中科院分区：
文献类型：
--
作者：
Li, Fang;Wang, Lingyun;Liu, Maili
用核磁共振波谱和分子动力学模拟方法研究了新型降压药Valsartan(VST)与十二烷基硫酸钠(SDS)胶束的相互作用。VST在溶液中有两种构象，通过酰胺键的trons/cis(构象A/B)异构化在核磁共振时间尺度上缓慢交换。我们认为，Sartan类药物在与AT(1)受体相互作用之前，可以结合并扩散到生物膜中。用十二烷基硫酸钠模拟膜环境来表征两种VST构象。H-1核磁共振化学位移分析、质子弛豫速率和自扩散系数测量表明，构象A与十二烷基硫酸钠具有较高的结合亲和力，是分布在SID胶束中的主要构象。通过NOE测定和分子动力学模拟确定了VST在胶束中的位置，表明VST的丁链和联苯基团与十二烷基硫酸酯的烷基通过疏水作用相互作用。分子动力学模拟发现构象A具有较好的结合自由能，这表明构象A相对集中的疏水表面是其与胶束亲和力较高的原因。我们的结果与Potamitis et最近对VST与AT(1)受体结合的模拟结果很好地一致。Al(J.Chem.信息模特。2009)，他们证明了构象A(他们定义中的反式构象)是与受体结合的构象。我们的研究结果表明，生物膜在VST活性状态的稳定中起着至关重要的作用。因此，了解沙坦类药物与膜环境的相互作用将有助于研究这些化合物与其受体的作用机制，并为开发新的药物发现方法提供洞察力。
The interaction of valsartan (VST), a novel antihypertensive drug, with sodium dodecyl Sulfate (SDS) micelles has been investigated using Nuclear Magnetic Resonance (NMR) spectroscopy and Molecular Dynamics (MD) Simulation. VST has two conformations in solution, exchanging slowly on the NMR time scale via the trons/cis (conformer A/B) isomerization of the amide bond. It is suggested that drugs in the sartan class incorporate and diffuse into biological membranes before they interact with AT(1) receptors. SDS is used to mimic the membrane environment to characterize two VST conformers. H-1 NMR chemical shift analysis, proton relaxation rates, and self-diffusion coefficient measurements suggest that conformer A has a higher binding affinity to SDS and is the dominant conformer distributed in the SIDS micelles. The location of VST in the micelles is determined by NOE measurements and by the MD Simulation, showing that the butyl chain and biphenyl groups of VST interact with the alkyl group of SDS through hydrophobic interactions. Preferable binding free energy is found for conformer A by the MD simulation, which demonstrates that the relatively concentrated hydrophobic Surface of conformer A is responsible for its higher affinity to the micelles. Our results are in good agreement with a recent Simulation of VST bound onto the AT(1) receptor by Potamitis et. al (J. Chem. Inf. Model. 2009) who demonstrate that conformer A (trans conformation in their definition) is the one binding to the receptor. The results presented in our study suggest that the biological membrane plays an essential role in stabilization of the active state of VST. Thus, understanding the interactions between the sartan drugs and the membrane environment should facilitate the studies of the functional mechanism of these compounds with their receptor and provide insight oil the development of new approaches for drug discovery.