Kuang Yaming Honors School, Nanjing University, 210023 Nanjing, China.
Institute for Brain Sciences, Nanjing University, 210023 Nanjing, China.
J Phys Chem B. 2021 May 27;125(20):5338-5345. doi: 10.1021/acs.jpcb.1c02436. Epub 2021 May 13.
Drug molecules either bind to membrane-bound targets or permeate through cell membranes to reach intracellular targets, and hence, their membrane partition and permeation are of great importance. Here, we studied the effects of cholesterol on the partition of amantadine, an antiflu drug molecule, into 1,2-dimyristoyl--glycero-3-phosphocholine bilayers using molecular dynamics simulations. The membrane partition of amantadine is sensitive to the cholesterol mole fraction (). In the absence of cholesterol, amantadine is stably bound in membranes, but at = 32%, it can escape to the aqueous phase, in agreement with recent experiments. The reduced membrane partition of amantadine at a high cholesterol content is mainly due to the perturbation of the bilayer structure and dynamics. Surrounding lipids stabilize amantadine by having their tails wrapped around the drug molecule, and this ability is compromised when cholesterol is present to increase the order in lipid tails. The atomic details on interactions with lipids and perturbations by cholesterol revealed here provide insight into membrane partition and delivery of drug molecules to their targets.
药物分子要么与膜结合靶标结合，要么穿透细胞膜到达细胞内靶标，因此，它们的膜分配和渗透非常重要。在这里，我们使用分子动力学模拟研究了胆固醇对金刚烷胺（一种抗流感药物分子）分配到 1,2-二肉豆蔻酰-sn-甘油-3-磷酸胆碱双层膜的影响。金刚烷胺的膜分配对胆固醇摩尔分数（）敏感。在没有胆固醇的情况下，金刚烷胺稳定地结合在膜中，但在 = 32%时，它可以逃到水相，这与最近的实验结果一致。在高胆固醇含量下，金刚烷胺的膜分配减少主要是由于双层结构和动力学的扰动。周围的脂质通过将其尾部包裹在药物分子上来稳定金刚烷胺，而当胆固醇存在以增加脂质尾部的有序性时，这种能力就会受到损害。这里揭示的与脂质相互作用的原子细节和胆固醇的扰动为药物分子向其靶标的膜分配和传递提供了深入了解。
