Laboratory of Chemometrics, Department of Chemistry, University of Perugia, Via Elce di Sotto 10, I-06123 Perugia, Italy.
J Med Chem. 2011 Mar 24;54(6):1740-51. doi: 10.1021/jm101421d. Epub 2011 Feb 22.
P-glycoprotein (Pgp or ABCB1) is an ABC transporter protein involved in intestinal absorption, drug metabolism, and brain penetration, and its inhibition can seriously alter a drug's bioavailability and safety. In addition, inhibitors of Pgp can be used to overcome multidrug resistance. Given this dual purpose, reliable in silico procedures to predict Pgp inhibition are of great interest. A large and accurate literature collection yielded more than 1200 structures; a model was then constructed using various molecular interaction field-based technologies, considering pharmacophoric features and those physicochemical properties related to membrane partitioning. High accuracy was demonstrated internally with two different validation sets and, moreover, using a number of molecules, for which Pgp inhibition was not experimentally available but was evaluated in-house. All of the validations confirmed the robustness of the model and its suitability to help medicinal chemists in drug discovery. The information derived from the model was rationalized as a pharmacophore for competitive Pgp inhibition.
P-糖蛋白（Pgp 或 ABCB1）是一种 ABC 转运蛋白，参与肠道吸收、药物代谢和脑穿透，其抑制作用可严重改变药物的生物利用度和安全性。此外，Pgp 的抑制剂可用于克服多药耐药性。鉴于这种双重用途，可靠的计算机预测 Pgp 抑制的程序非常重要。从大量且准确的文献中收集了超过 1200 种结构；然后使用各种基于分子相互作用场的技术构建了一个模型，考虑了药效特征和与膜分配相关的物理化学性质。该模型通过两个不同的验证集进行了内部验证，并且使用了一些没有实验可获得但在内部进行了评估的 Pgp 抑制的分子，证明了其具有很高的准确性。所有的验证都证实了该模型的稳健性及其适合帮助药物化学家进行药物发现。从模型中得出的信息被合理化，作为竞争性 Pgp 抑制的药效基团。
