In Silico Lead Discovery

Application of In Silico Methods to Study ABC Transporters Involved in Multidrug Resistance

Author(s): Ilza Pajeva and Michael Wiese

Pp: 144-162 (19)

DOI: 10.2174/978160805142711101010144

* (Excluding Mailing and Handling)


ABC transporters are involved in variety of processes of physiological and clinical significance. Besides their function as natural physiological protectors of the living organisms against xenobiotics, they play a crucial role in drug pharmacokinetics and for the multidrug resistance in tumor cells. The in silico modeling of ABC transporters is extensively developing in the recent years making use of increasing data about 3D structures of transport proteins. The chapter describes the most recent achievements in the computational studies starting from ligand-based design approaches and classification algorithms to homology modeling and docking of ligands. Many of the models show a satisfying performance shading light on the structure-function relationships of the proteins and their substrates and inhibitors, as well as generating hypotheses of ligand-protein interactions and helping in design of further experimental studies. However, a number of problems related to reliability of the experimental data used for modeling and computational methodologies applied limit the applicability of these methods for virtual ligand screening. First attempts towards docking of ligands into transporter binding sites are discussed to illustrate these limitations.

Keywords: ABC transporters, multidrug resistance, QSAR, pharmacophore modeling, homology models, docking

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