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In silico structure-based screening of versatile P-glycoprotein inhibitors using polynomial empirical scoring functions

Authors Shityakov S, Förster C

Received 16 October 2013

Accepted for publication 15 November 2013

Published 24 March 2014 Volume 2014:7 Pages 1—9

DOI https://doi.org/10.2147/AABC.S56046

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Sergey Shityakov, Carola Förster

Department of Anesthesia and Critical Care, University of Würzburg, Würzburg, Germany

Abstract: P-glycoprotein (P-gp) is an ATP (adenosine triphosphate)-binding cassette transporter that causes multidrug resistance of various chemotherapeutic substances by active efflux from mammalian cells. P-gp plays a pivotal role in limiting drug absorption and distribution in different organs, including the intestines and brain. Thus, the prediction of P-gp–drug interactions is of vital importance in assessing drug pharmacokinetic and pharmacodynamic properties. To find the strongest P-gp blockers, we performed an in silico structure-based screening of P-gp inhibitor library (1,300 molecules) by the gradient optimization method, using polynomial empirical scoring (POLSCORE) functions. We report a strong correlation (r2=0.80, F=16.27, n=6, P<0.0157) of inhibition constants (Kiexp or pKiexp; experimental Ki or negative decimal logarithm of Kiexp) converted from experimental IC50 (half maximal inhibitory concentration) values with POLSCORE-predicted constants (KiPOLSCORE or pKiPOLSCORE), using a linear regression fitting technique. The hydrophobic interactions between P-gp and selected drug substances were detected as the main forces responsible for the inhibition effect. The results showed that this scoring technique might be useful in the virtual screening and filtering of databases of drug-like compounds at the early stage of drug development processes.

Keywords: ATP-binding cassette transporter, P-gp inhibitors, multidrug resistance, molecular docking, POLSCORE

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