Department of Chemistry - BMC, Uppsala University, Box 576, SE-751 23, Uppsala, Sweden.
Chemistry. 2023 Feb 7;29(8):e202202798. doi: 10.1002/chem.202202798. Epub 2022 Dec 14.
The ability to adjust conformations in response to the polarity of the environment, i.e. molecular chameleonicity, is considered to be important for conferring both high aqueous solubility and high cell permeability to drugs in chemical space beyond Lipinski's rule of 5. We determined the conformational ensembles populated by the antiviral drugs asunaprevir, simeprevir, atazanavir and daclatasvir in polar (DMSO-d ) and non-polar (chloroform) environments with NMR spectroscopy. Daclatasvir was fairly rigid, whereas the first three showed large flexibility in both environments, that translated into major differences in solvent accessible 3D polar surface area within each conformational ensemble. No significant differences in size and polar surface area were observed between the DMSO-d and chloroform ensembles of these three drugs. We propose that such flexible compounds are characterized as "partial molecular chameleons" and hypothesize that their ability to adopt conformations with low polar surface area contributes to their membrane permeability and oral absorption.
药物分子能够根据环境极性进行构象调整，即分子拟态性，这被认为对于赋予化学空间中超出 Lipinski 五规则的药物高水溶性和高细胞通透性非常重要。我们通过 NMR 光谱法确定了抗病毒药物asunaprevir、simeprevir、atazanavir 和 daclatasvir 在极性（DMSO-d）和非极性（氯仿）环境中的构象。Daclatasvir 相当刚性，而前三种药物在两种环境中都表现出较大的灵活性，这导致每个构象集中溶剂可及的三维极性表面积存在较大差异。这三种药物在 DMSO-d 和氯仿环境中的集合尺寸和极性表面积没有明显差异。我们提出，这种灵活的化合物被称为“部分分子拟态物”，并假设它们能够采用低极性表面积的构象有助于它们的膜通透性和口服吸收。
