title: Multidrug resistance ABC transporter structure predictions by homology modeling approaches.
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.
authors.affiliation: ISPB, Université Lyon1, 69008 Lyon, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Honorat
authors.forename: Pierre
authors.initials: P
authors.lastname: Falson
authors.forename: Raphael
authors.initials: R
authors.lastname: Terreux
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
authors.forename: Léa
authors.initials: L
authors.lastname: Payen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D018432:Drug Resistance, Multiple; D006801:Humans; D010599:Pharmacokinetics; D040681:Structural Homology, Protein
chemical_list: D018528:ATP-Binding Cassette Transporters