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

Journal of Computer-aided Molecular Design
Sankalp JainGerhard F Ecker

Abstract

The bile salt export pump (BSEP) actively transports conjugated monovalent bile acids from the hepatocytes into the bile. This facilitates the formation of micelles and promotes digestion and absorption of dietary fat. Inhibition of BSEP leads to decreased bile flow and accumulation of cytotoxic bile salts in the liver. A number of compounds have been identified to interact with BSEP, which results in drug-induced cholestasis or liver injury. Therefore, in silico approaches for flagging compounds as potential BSEP inhibitors would be of high value in the early stage of the drug discovery pipeline. Up to now, due to the lack of a high-resolution X-ray structure of BSEP, in silico based identification of BSEP inhibitors focused on ligand-based approaches. In this study, we provide a homology model for BSEP, developed using the corrected mouse P-glycoprotein structure (PDB ID: 4M1M). Subsequently, the model was used for docking-based classification of a set of 1212 compounds (405 BSEP inhibitors, 807 non-inhibitors). Using the scoring function ChemScore, a prediction accuracy of 81% on the training set and 73% on two external test sets could be obtained. In addition, the applicability domain of the models was assessed based on Euc...Continue Reading

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Citations

Aug 24, 2018·Clinical Pharmacology and Therapeutics·J Gerry KennaUNKNOWN International Transporter Consortium
Dec 24, 2018·International Journal of Molecular Sciences·Natesh SinghGerhard F Ecker
Feb 5, 2021·Scientific Reports·Meng-Yu ZhangXian-Ming Xia
Jan 21, 2021·International Journal of Molecular Sciences·Muhammad Imran SohailPeter Chiba
Jan 28, 2021·Journal of Chemical Information and Modeling·Kevin S McLoughlinJames M Brase
Sep 6, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Pavlo V ZadorozhniiAleksandr V Kharchenko
Oct 6, 2021·ACS Pharmacology & Translational Science·Sankalp JainAlexey V Zakharov

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Methods Mentioned

BETA
X-ray
glycosylation
structure-based prediction

Software Mentioned

SVL house
J48
Schrödinger Suite
LibSVMand
Prime
WEKA
GOLD suit
STAin maestro
Protein Preparation Wizard
Gromacs

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