Flagging Drugs That Inhibit the Bile Salt Export Pump

Abstract

The bile salt export pump (BSEP) is an ABC-transporter expressed at the canalicular membrane of hepatocytes. Its physiological role is to expel bile salts into the canaliculi from where they drain into the bile duct. Inhibition of this transporter may lead to intrahepatic cholestasis. Predictive computational models of BSEP inhibition may allow for fast identification of potentially harmful compounds in large databases. This article presents a predictive in silico model based on physicochemical descriptors that is able to flag compounds as potential BSEP inhibitors. This model was built using a training set of 670 compounds with available BSEP inhibition potencies. It successfully predicted BSEP inhibition for two independent test sets and was in a further step used for a virtual screening experiment. After in vitro testing of selected candidates, a marketed drug, bromocriptin, was identified for the first time as BSEP inhibitor. This demonstrates the usefulness of the model to identify new BSEP inhibitors and therefore potential cholestasis perpetrators. Just Accepted "Just Accepted" manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides "Just Accepted" as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. "Just Accepted" manuscripts appear in full in PDF format accompanied by an HTML abstract. "Just Accepted" manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). "Just Accepted" is an optional service offered to authors. Therefore, the "Just Accepted" Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the "Just Accepted" Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these "Just Accepted" manuscripts. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 Table of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 1 Flagging drugs that inhibit the bile salt export pump AbstractThe bile salt export pump (BSEP) is an ABC-transporter expressed at the canalicular membrane of hepa...

Structure based classification for bile salt export pump (BSEP) inhibitors using comparative structural modeling of human BSEP

“…Respective confusion matrix parameters and other performance measures are summarized in Table 1. The ChemScore docking run using Xscore as rescoring function retrieved the best performing model with AUC (0.918) and MCC (0.689) measures comparable to the models developed by Warner et al [24] and Montanari et al [25]. This model accurately predicted 88% of the training set compounds and 72% of the external test set compounds derived from Pedersen et al [34] as well as 77% of a set of AstraZeneca internal compounds.…”

“…Removing the overlapping compounds from the first two datasets resulted in 638 compounds (248 inhibitors and 390 non-inhibitors). All datasets were standardized using the protocol previously described in Montanari et al [25] and Pinto et al [35]. …”

“…With respect to BSEP, QSAR modeling was applied by Warner et al [24] in which a support vector machine (SVM) model provided the highest accuracy of 87% in the classification of BSEP inhibitors and non-inhibitors on a dataset of 624 compounds [24]. Our group recently published a classification model based on a set of 670 compounds, which allowed the identification of bromocriptine as a BSEP inhibitor [25]. With first X-ray structures of ABC-transporters being published, also structure-based models became available.…”

Predicting Drug-Induced Cholestasis with the Help of Hepatic Transporters—An in Silico Modeling Approach

“…For the latter we used our in house classification models for BSEP, 37 BCRP, 38 P-gp, 38 OATP1B1, and OATP1B3. 39 …”

Empowering pharmacoinformatics by linked life science data

“…Currently, each of our computational projects, be it on ion channels, such as TRPV1 [56] and GABAA [24], or transporters, such as P-gp [unpublished], BSEP [37], BCRP [57], and GAT3 [unpublished], is validated in vitro either in-house or outsourced.…”