Shoji Alyson, Kang Christopher, Fujioka Kazuumi, Rose John P, Sun Rui
Department of Chemistry, The University of Hawai'i at Manoa, Honolulu, Hawaii 96822, United States.
DDCS, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
J Chem Theory Comput. 2022 Jan 11;18(1):503-515. doi: 10.1021/acs.jctc.1c00661. Epub 2021 Dec 1.
A protocol that accurately assesses the intestinal permeability of small molecule compounds plays an essential role in decreasing the cost and time in inventing a new drug. This manuscript presents a novel computational method to study the passive permeation of small molecule drugs based on the inhomogeneous solubility-diffusion model. The multidimensional free energy surface of the drug transiting through a lipid bilayer is computed with transition-tempered metadynamics that accurately captures the mechanisms of passive permeation. The permeability is computed by following the diffusion motion of the drug molecules along the minimal free energy path found on the multidimensional free energy surface. This computational method is assessed by studying the permeability of five small molecule drugs (ketoprofen, naproxen, metoprolol, propranolol, and salicylic acid). The results demonstrate a remarkable agreement between the computed permeabilities and those measured with the intestinal assay. The method reported in this manuscript also reproduces the permeability measured from the intestinal assay () better than the cell-based assays (e.g., PAMPA and Caco-2) do. In addition, the multidimensional free energy surface reveals the interplay between the structure of the small molecule and its permeability, shedding light on strategies of drug optimization.
一种能够准确评估小分子化合物肠道通透性的方案，在降低新药研发成本和时间方面起着至关重要的作用。本文提出了一种基于非均匀溶解度-扩散模型研究小分子药物被动渗透的新计算方法。利用过渡温度元动力学计算药物穿过脂质双层的多维自由能表面，该方法能准确捕捉被动渗透机制。通过跟踪药物分子沿多维自由能表面上找到的最小自由能路径的扩散运动来计算渗透率。通过研究五种小分子药物（酮洛芬、萘普生、美托洛尔、普萘洛尔和水杨酸）的渗透率来评估这种计算方法。结果表明，计算得到的渗透率与肠道试验测量的渗透率之间存在显著一致性。本文报道的方法在重现肠道试验测量的渗透率方面也比基于细胞的试验（如PAMPA和Caco-2）做得更好。此外，多维自由能表面揭示了小分子结构与其渗透率之间的相互作用，为药物优化策略提供了线索。
