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WIREs Comput Mol Sci
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Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies

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One of the greatest threats to cancer treatment is the development, by some tumors, of resistance to the pharmacological action of several structurally unrelated cytotoxic agents—multidrug resistance (MDR). As P‐glycoprotein (P‐gp) is one of the most studied ATP‐dependent efflux pumps that are frequently involved in drug efflux from cancer cells, the development of MDR modulators with the ability to inhibit P‐gp efflux is considered a promising approach for overcoming MDR. However, the development of P‐gp modulators have been hampered due to the absence of knowledge on the intrinsic molecular aspects by which efflux occurs, namely the specific steps that correlates drug recognition, ATP binding and efflux‐related conformational changes. Experimental evidences for these processes are also difficult to obtain and only provide small pieces of information that need to be assembled for better comprehension of a wider and complex process that is drug efflux. A promising alternative relies on cutting‐edge computational techniques to provide new insights on key aspects that are determinant to understand how P‐gp efflux can be effectively reversed. With the contribution of ligand‐based or structure‐based computational methods, P‐gp drug efflux is slowly becoming a dynamic and reactive process rather than a simple response to drug binding, with the complex architecture of ABC transporters playing a determinant role not only in drug recognition but in the coordination of ATP‐driven conformational changes that ultimately drives drug efflux. The major enlightenments that computational studies provided toward a better comprehension of MDR and P‐gp efflux phenomena are hereby described. WIREs Comput Mol Sci 2015, 5:27–55. doi: 10.1002/wcms.1196

World cancer incidence in 2012 (adapted from Ref ; http://globocan.iarc.fr/Pages/Map.aspx).
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New proposed model for the ATP catalytic cycle. The ATP‐binding pocket is formed by Walker A motifs of NBD1 (WA1) and NBD2 (WA2) with the signature motifs of the opposite NBD2 (S2) and NBD1 (S1). Pore opening/closing refers to the outward‐facing structure.
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Two models proposed for the catalytic cycle: (a) Switch and (b) Constant Contact models. The ATP‐binding pocket is formed by Walker A motifs of NBD1 (WA1) and NBD2 (WA2) with the signature motifs of the opposite NBD2 (S2) and NBD1 (S1). Pore opening/closing refers to the outward‐facing structure.
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ABC transporters with available crystallographic structures [based on crystallographic structures 2HYD (Sav1866), 3B5Y (MsbA), 3G5U, and 4F4C (P‐gp) from http://www.rcsb.org].
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Proposed models for ABC transporters efflux: (a) membranar pore; (b) flippase, and (c) hydrophobic vacuum cleaner.
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Membrane topology models of (a) ABCB1, (b) ABCC1, and (c) ABCG2.
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Schematic diagram of resistance to drugs: (1) decreased influx or increased efflux/sequestration, (2) disruption of apoptosis or alterations in cell cycle checkpoints, (3) activation of drug metabolism, (4) increase in DNA repair, or (5) mutations in cellular targets.
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