Institute of General, Inorganic and Theoretical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, Innsbruck A-6020 Austria.
J Chem Inf Model. 2020 Jul 27;60(7):3508-3517. doi: 10.1021/acs.jcim.0c00280. Epub 2020 Jun 29.
The relation of surface polarity and conformational preferences is decisive for cell permeability and thus bioavailability of macrocyclic drugs. Here, we employ grid inhomogeneous solvation theory (GIST) to calculate solvation free energies for a series of six macrocycles in water and chloroform as a measure of passive membrane permeability. We perform accelerated molecular dynamics simulations to capture a diverse structural ensemble in water and chloroform, allowing for a direct profiling of solvent-dependent conformational preferences. Subsequent GIST calculations facilitate a quantitative measure of solvent preference in the form of a transfer free energy, calculated from the ensemble-averaged solvation free energies in water and chloroform. Hence, the proposed method considers how the conformational diversity of macrocycles in polar and apolar solvents translates into transfer free energies. Following this strategy, we find a striking correlation of 0.92 between experimentally determined cell permeabilities and calculated transfer free energies. For the studied model systems, we find that the transfer free energy exceeds the purely water-based solvation free energies as a reliable estimate of cell permeability and that conformational sampling is imperative for a physically meaningful model. We thus recommend this purely physics-based approach as a computational tool to assess cell permeabilities of macrocyclic drug candidates.
表面极性和构象偏好的关系对细胞通透性有决定性影响，从而影响大环药物的生物利用度。在这里，我们采用非均匀网格溶剂化理论（GIST）来计算一系列六种大环在水中和氯仿中的溶剂化自由能，以此作为衡量被动膜通透性的指标。我们进行加速分子动力学模拟，以捕获水中和氯仿中的多种结构构象，从而可以直接分析溶剂依赖性构象偏好。随后的 GIST 计算以转移自由能的形式提供了溶剂偏好的定量衡量，该自由能是通过在水中和氯仿中的溶剂化自由能的均方值计算得出的。因此，所提出的方法考虑了大环在极性和非极性溶剂中的构象多样性如何转化为转移自由能。按照这一策略，我们发现实验测定的细胞通透性和计算的转移自由能之间存在 0.92 的惊人相关性。对于所研究的模型系统，我们发现转移自由能超过了基于纯水的溶剂化自由能，这是细胞通透性的可靠估计，并且构象采样对于具有物理意义的模型至关重要。因此，我们建议将这种纯基于物理的方法作为评估大环候选药物细胞通透性的计算工具。
