Molecular Modelling Of BCRP (ABCG2) Multidrug Resistance Protein And Docking Of New Camptothecin Analogues

The ABC transporter superfamily is among the largest and most broadly expressed protein families. Members of this family use the energy stored in ATP molecules to actively extrude a variety of substrates from cells, including exogenous compounds such as drugs, metabolites, peptides, steroids, ions and phospholipids. So far, the best known and characterized major drugs transporters, have been studied in details with respect to their structure and function. It has been showed that ATP-dependent transporters can cause resistance in cancer cells by actively extruding the clinically relevant chemotherapic drugs. There is accumulating evidence that active export of anticancer drugs from cells by means of specific transporters is one of the major mechanism of drug resistance. Camptothecin (CPT) and its derivatives has been proven to be effective against a broad set of tumors. The CPT target is the human DNA topoisomerase I, an enzyme that changes the topological state of the DNA double helix during biological activity of the cell. Here we report a computaional study of the interaction mechanism between a set of biochemically and clinically relevant campthotecin ligands. A series of multiple docking simulations were carried out using the topotecan, gimatecan and irinotecan CPT derivatives as possible ligands, and a homology model of ABCG2 transporter was used as target molecule. Our results show that the camptothecin derivatives dock to distinct sites located in the trans-membrane region of the transporter molecule. The chemical nature of the substitutions at position A of the CPT analogues used in this study is also analyzed to identify the structural prerequisites responsible for the relative selectivity of the ligand. The structural basis of ligand binding may help design new CPT analogues with reduced side effects and higher affinity.