Biosciences and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California 94550, United States.
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York 10065, United States.
J Med Chem. 2020 Oct 22;63(20):11809-11818. doi: 10.1021/acs.jmedchem.0c00958. Epub 2020 Oct 1.
Partitioning of bioactive molecules, including drugs, into cell membranes may produce indiscriminate changes in membrane protein function. As a guide to safe drug development, it therefore becomes important to be able to predict the bilayer-perturbing potency of hydrophobic/amphiphilic drugs candidates. Toward this end, we exploited gramicidin channels as molecular force probes and developed and assays to measure drugs' bilayer-modifying potency. We examined eight drug-like molecules that were found to enhance or suppress gramicidin channel function in a thick 1,2-dierucoyl--glycero-3-phosphocholine (DCPC) but not in thin 1,2-dioleoyl--glycero-3-phosphocholine (DCPC) lipid bilayer. The mechanism underlying this difference was attributable to the changes in gramicidin dimerization free energy by drug-induced perturbations of lipid bilayer physical properties and bilayer-gramicidin interactions. The combined and approaches, which allow for predicting the perturbing effects of drug candidates on membrane protein function, have implications for preclinical drug safety assessment.
生物活性分子（包括药物）在细胞膜中的分配可能会导致膜蛋白功能的无差别改变。因此，能够预测疏水性/两亲性药物候选物对双层膜的破坏能力，对于安全的药物开发就显得尤为重要。为此，我们利用短杆菌肽通道作为分子力探针，并开发了 和 测定法来测量药物对双层膜的修饰能力。我们研究了 8 种类似药物的分子，这些分子在厚的 1,2-二油酰基- -甘油-3-磷酸胆碱（DCPC）中增强或抑制短杆菌肽通道功能，但在薄的 1,2-二油酸基- -甘油-3-磷酸胆碱（DCPC）脂质双层中没有作用。这种差异的根本原因是药物对脂质双层物理性质和双层-短杆菌肽相互作用的干扰改变了短杆菌肽二聚化自由能。这两种方法结合起来，可以预测药物候选物对膜蛋白功能的干扰作用，这对临床前药物安全性评估具有重要意义。
