title: Predicting P-glycoprotein-mediated drug transport based on support vector machine and three-dimensional crystal structure of P-glycoprotein.
abstract: Human P-glycoprotein (P-gp) is an ATP-binding cassette multidrug transporter that confers resistance to a wide range of chemotherapeutic agents in cancer cells by active efflux of the drugs from cells. P-gp also plays a key role in limiting oral absorption and brain penetration and in facilitating biliary and renal elimination of structurally diverse drugs. Thus, identification of drugs or new molecular entities to be P-gp substrates is of vital importance for predicting the pharmacokinetics, efficacy, safety, or tissue levels of drugs or drug candidates. At present, publicly available, reliable in silico models predicting P-gp substrates are scarce. In this study, a support vector machine (SVM) method was developed to predict P-gp substrates and P-gp-substrate interactions, based on a training data set of 197 known P-gp substrates and non-substrates collected from the literature. We showed that the SVM method had a prediction accuracy of approximately 80% on an independent external validation data set of 32 compounds. A homology model of human P-gp based on the X-ray structure of mouse P-gp as a template has been constructed. We showed that molecular docking to the P-gp structures successfully predicted the geometry of P-gp-ligand complexes. Our SVM prediction and the molecular docking methods have been integrated into a free web server (http://pgp.althotas.com), which allows the users to predict whether a given compound is a P-gp substrate and how it binds to and interacts with P-gp. Utilization of such a web server may prove valuable for both rational drug design and screening.
authors: Virtua Drug Ltd, Budapest, Hungary.
authors: Zsolt
authors: Z
authors: Bikadi
authors: Istvan
authors: I
authors: Hazai
authors: David
authors: D
authors: Malik
authors: Katalin
authors: K
authors: Jemnitz
authors: Zsuzsa
authors: Z
authors: Veres
authors: Peter
authors: P
authors: Hari
authors: Zhanglin
authors: Z
authors: Ni
authors: Tip W
authors: TW
authors: Loo
authors: David M
authors: DM
authors: Clarke
authors: Eszter
authors: E
authors: Hazai
authors: Qingcheng
authors: Q
authors: Mao
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000378:metabolism*; D001692:Biological Transport; D018360:Crystallography, X-Ray; D019992:Databases as Topic; D006801:Humans; D020407:Internet; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D015203:Reproducibility of Results; D012235:Rhodamines / Q000737:chemistry; D060388:Support Vector Machine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations; D012235:Rhodamines; C029773:rhodamine B