论文标题
数据驱动的方程式用于药物和膜的药物渗透性
Data-driven equation for drug-membrane permeability across drugs and membranes
论文作者
论文摘要
药物疗效取决于其渗透到整个细胞膜上的能力。我们考虑被动药物渗透率系数的预测。除了与疏水性广泛认识的相关性之外,我们还考虑了被动渗透与酸度之间的功能关系。为了发现易于解释的方程式可以很好地解释数据,我们使用了最近提出的确定独立筛选和稀疏操作员(SISSO),这是一种将符号回归与压缩感应结合在一起的人工智能技术。我们的研究基于一个从粗粒模拟中提取的40万个小分子的硅数据集中。我们通过分析了几种渐近酸度制度中对不均匀溶解度扩散模型的分析,合理化了SISSO建议的方程式。我们进一步将分析扩展到对脂质膜组成的依赖性。脂肪尾不饱和起着关键作用,但出乎意料的是逐步贡献而不是按比例贡献。我们的结果与先前观察到的渗透率变化一致,这表明液体序列(LD)和液体有序(LO)渗透之间的区别。共同通过分析得出的渐近线建立并验证了在药物和脂质尾化学上都被动渗透性的准确,适用且可解释的方程式的压缩感测。
Drug efficacy depends on its capacity to permeate across the cell membrane. We consider the prediction of passive drug-membrane permeability coefficients. Beyond the widely recognized correlation with hydrophobicity, we additionally consider the functional relationship between passive permeation and acidity. To discover easily interpretable equations that explain the data well, we use the recently proposed sure-independence screening and sparsifying operator (SISSO), an artificial-intelligence technique that combines symbolic regression with compressed sensing. Our study is based on a large in silico dataset of 0.4 million small molecules extracted from coarse-grained simulations. We rationalize the equation suggested by SISSO via an analysis of the inhomogeneous solubility-diffusion model in several asymptotic acidity regimes. We further extend our analysis to the dependence on lipid-membrane composition. Lipid-tail unsaturation plays a key role, but surprisingly contributes stepwise rather than proportionally. Our results are in line with previously observed changes in permeability, suggesting the distinction between liquid-disordered (Ld) and liquid-ordered (Lo) permeation. Together, compressed sensing with analytically derived asymptotes establish and validate an accurate, broadly applicable, and interpretable equation for passive permeability across both drug and lipid-tail chemistry.