Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, United States.
Mol Pharm. 2010 Dec 6;7(6):2240-54. doi: 10.1021/mp100233v. Epub 2010 Nov 1.
The human apical sodium dependent bile acid transporter (hASBT) reabsorbs gram quantities of bile acid daily and is a potential prodrug target to increase oral drug absorption. In the absence of a high resolution hASBT crystal structure, 3D-QSAR modeling may prove beneficial in designing prodrug targets to hASBT. The objective was to derive a conformationally sampled pharmacophore 3D-QSAR (CSP-SAR) model for the uptake of bile acid conjugates by hASBT. A series of bile acid conjugates of glutamyl chenodeoxycholate were evaluated in terms of K(m) and normalized V(max) (normV(max)) using hASBT-MDCK cells. All monoanionic conjugates were potent substrates. Dianions, cations and zwitterions, which bound with a high affinity, were not substrates. CSP-SAR models were derived using structural and physicochemical descriptors, and evaluated via cross validation. The best CSP-SAR model for K(m) included two structural and two physiochemical descriptors, where substrate hydrophobicity enhanced affinity. A best CSP-SAR model for K(m)/normV(max) employed one structural and three physicochemical descriptors, also indicating hydrophobicity enhanced efficiency. Overall, the bile acid C-24 region accommodated a range of substituted anilines, provided a single negative charge was present near C-24. In comparing uptake findings to prior inhibition results, increased hydrophobicity enhanced activity, with dianions and zwitterions hindering activity.
人顶钠依赖性胆汁酸转运蛋白（hASBT）每天重吸收克数量的胆汁酸，是增加口服药物吸收的潜在前药靶点。由于缺乏高分辨率的 hASBT 晶体结构，3D-QSAR 建模可能有助于设计针对 hASBT 的前药靶标。本研究旨在为 hASBT 摄取胆汁酸缀合物推导构象采样药效团 3D-QSAR（CSP-SAR）模型。使用 hASBT-MDCK 细胞，以 K(m)和归一化 V(max)（normV(max)）评估一系列谷氨酸鹅脱氧胆酸缀合物。所有单阴离子缀合物都是有效的底物。二阴离子、阳离子和两性离子，由于与高亲和力结合，不是底物。使用结构和物理化学描述符推导 CSP-SAR 模型，并通过交叉验证进行评估。用于 K(m)的最佳 CSP-SAR 模型包括两个结构和两个物理化学描述符，其中底物疏水性增强了亲和力。用于 K(m)/normV(max)的最佳 CSP-SAR 模型采用了一个结构和三个物理化学描述符，也表明疏水性增强了效率。总体而言，胆汁酸 C-24 区域可容纳一系列取代的苯胺，只要 C-24 附近存在一个单一的负电荷。将摄取发现与先前的抑制结果进行比较，疏水性增加可增强活性，二阴离子和两性离子则会阻碍活性。
