title: Combined QSAR and molecule docking studies on predicting P-glycoprotein inhibitors.
abstract: P-glycoprotein (P-gp) is an ATP-binding cassette multidrug transporter. The over expression of P-gp leads to the development of multidrug resistance (MDR), which is a major obstacle to effective treatment of cancer. Thus, designing effective P-gp inhibitors has an extremely important role in the overcoming MDR. In this paper, both ligand-based quantitative structure-activity relationship (QSAR) and receptor-based molecular docking are used to predict P-gp inhibitors. The results show that each method achieves good prediction performance. According to the results of tenfold cross-validation, an optimal linear SVM model with only three descriptors is established on 857 training samples, of which the overall accuracy (Acc), sensitivity, specificity, and Matthews correlation coefficient are 0.840, 0.873, 0.813, and 0.683, respectively. The SVM model is further validated by 418 test samples with the overall Acc of 0.868. Based on a homology model of human P-gp established, Surflex-dock is also performed to give binding free energy-based evaluations with the overall accuracies of 0.823 for the test set. Furthermore, a consensus evaluation is also performed by using these two methods. Both QSAR and molecular docking studies indicate that molecular volume, hydrophobicity and aromaticity are three dominant factors influencing the inhibitory activities.
authors: Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing, 400044, China.
authors: Wen
authors: W
authors: Tan
authors: Hu
authors: H
authors: Mei
authors: Li
authors: L
authors: Chao
authors: Tengfei
authors: T
authors: Liu
authors: Xianchao
authors: X
authors: Pan
authors: Mao
authors: M
authors: Shu
authors: Li
authors: L
authors: Yang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D018432:Drug Resistance, Multiple; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D060388:Support Vector Machine
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D004364:Pharmaceutical Preparations