Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Zographou, Athens 15771, Greece.
National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, 48 Vas. Constantinou, Athens 11635, Greece.
Mol Inform. 2011 Dec;30(11-12):973-85. doi: 10.1002/minf.201100077. Epub 2011 Dec 1.
Aliskiren is the first orally active, direct renin inhibitor to be approved for the treatment of hypertension. Its structure elucidation and conformational analysis were explored using 1D and 2D NMR spectroscopy, as well as random search and molecular dynamics (MD) simulations. For the first time, MD calculations have also been performed for aliskiren at the receptor site, in order to reveal its molecular basis of action. It is suggested that aliskiren binds in an extended conformation and is involved in several stabilizing hydrogen bonding interactions with binding cavity (Asp32/255, Gly34) and other binding-cavity (Arg74, Ser76, Tyr14) residues. Of paramount importance is the finding of a loop consisting of residues around Ser76 that determines the entrapping of aliskiren into the active site of renin. The details of this mechanism will be the subject of a subsequent study. Additionally molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculations for the aliskiren-renin complex provided insight into the binding mode of aliskiren by identifying van der Waals and nonpolar contribution to solvation as the main components of favorable binding interactions.
阿利克仑是首个获准用于治疗高血压的口服、直接肾素抑制剂。采用一维和二维 NMR 光谱、随机搜索和分子动力学（MD）模拟对其结构进行了阐述和分析。首次还在受体部位对阿利克仑进行了 MD 计算，以揭示其作用的分子基础。研究表明，阿利克仑呈伸展构象结合，与结合腔（Asp32/255、Gly34）和其他结合腔（Arg74、Ser76、Tyr14）残基形成多个稳定氢键相互作用。至关重要的是发现了一个由 Ser76 周围残基组成的环，该环决定了阿利克仑被束缚在肾素的活性部位。这一机制的细节将是后续研究的主题。此外，对阿利克仑-肾素复合物的分子力学泊松-玻尔兹曼表面积（MM-PBSA）自由能计算，通过确定范德华力和非极性对溶剂化的贡献是有利结合相互作用的主要成分，深入了解了阿利克仑的结合模式。
