Multidrug Resistance ABC Transporter Structure Predictions by Homology Modeling Approaches

Author(s): Mylene Honorat, Pierre Falson, Raphael Terreux, Attilio Di Pietro, Charles Dumontet, Lea Payen

Journal Name: Current Drug Metabolism

Volume 12 , Issue 3 , 2011

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Abstract:

Human multidrug resistance ABC transporters are ubiquitous membrane proteins responsible for the efflux of multiple, endogenous or exogenous, compounds out of the cells, and therefore they are involved in multi-drug resistance phenotype (MDR). They thus deeply impact the pharmacokinetic parameters and toxicity properties of drugs. A great pressure to develop inhibitors of these pumps is carried out, by either ligand-based drug design or (more ideally) structure-based drug design. In that goal, many biochemical studies have been carried out to characterize their transport functions, and many efforts have been spent to get high-resolution structures. Currently, beside the 3D-structures of bacterial ABC transporters Sav1866 and MsbA, only the mouse ABCB1 complete structure has been published at high-resolution, illustrating the tremendous difficulty in getting such information, taking into account that the human genome accounts for 48 ABC transporters encoding genes. Homology modeling is consequently a reasonable approach to overcome this obstacle. The present review describes, in the first part, the different approaches which have been published to set up human ABC pump 3D-homology models allowing the localization of binding sites for drug candidates, and the identification of critical residues therein. In a second part, the review proposes a more accurate strategy and practical keys to use such biological tools for initiating structure-based drug design.

Keywords: Human, ABC transporter, 3D-Structure, Homology, Modeling, Docking, Drug Disposition, Multidrug resistance, pharmacokinetic parameters, multi-drug resistance phenotype (MDR), structure-based drug design

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Article Details

VOLUME: 12
ISSUE: 3
Year: 2011
Page: [268 - 277]
Pages: 10
DOI: 10.2174/138920011795101804
Price: $65

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