高血压,由血管紧张素II受体1型(AT1R)介导,尽管发现了新疗法,但仍然是过早死亡的主要原因,强调深入了解药物-AT1R识别机制以及膜环境对药物与AT1R相互作用的影响的重要性。在这里,我们使用由60:40mol%组成的模型膜的分子动力学模拟研究了胆固醇-脂质-坎地沙坦和AT1R的相互作用。DPPC:胆固醇,坎地沙坦和AT1R,模拟肌膜中的生理胆固醇浓度。60:40mol%的模型膜的模拟。使用DOSYNMR实验进一步验证DPPC:胆固醇。有趣的是,我们的结果表明,胆固醇在AT1R功能中的重要作用是通过受体中的胆固醇共识基序(CCM)施加的,这在药物结合过程中可能至关重要。坎地沙坦通过掺入脂质双层向AT1R扩散,似乎被胆固醇的存在所阻碍。然而,其对AT1R的直接途径可能是通过CCM上的胆固醇结合在N端诱导的运动性来促进的。这些新见解可能为开发更有效的抗高血压药物铺平道路。
Hypertension, mediated by the Angiotensin II receptor type 1 (AT1R), is still the major cause of premature death despite the discovery of novel therapeutics, highlighting the importance of an in depth understanding of the drug-AT1R recognition mechanisms coupled with the impact of the membrane environment on the interaction of drugs with AT1R. Herein, we examine the interplay of cholesterol-lipid-candesartan and the AT1R using Molecular Dynamics simulations of a model membrane consisting of 60:40 mol%. DPPC:cholesterol, candesartan and the AT1R, mimicking the physiological cholesterol concentration in sarcolemma membranes. The simulations of the model membrane of 60:40 mol%. DPPC:cholesterol were further validated using DOSY NMR experiments. Interestingly, our results suggest a significant role of cholesterol in the AT1R function imposed through a Cholesterol
Consensus Motif (CCM) in the receptor, which could be crucial in the drug binding process. Candesartan diffusion towards AT1R through incorporation into lipid bilayers, appears to be retarded by the presence of cholesterol. However, its direct approach towards AT1R may be facilitated through the mobility induced on the N-terminus by the cholesterol binding on the CCM these novel insights could pave the way towards the development of more potent pharmaceutical agents to combat hypertension more effectively.