Emerging New Technology: QSAR Analysis and MO Calculation to Characterize Interactions of Protein Kinase Inhibitors with the Human ABC Transporter, ABCG2 (BCRP)

Summary:Protein kinases are potential drug targets for the treatment of a variety of diseases, including cancer. In particular, specific tyrosine kinase inhibitors are rapidly being developed as new drugs for the inhibition of malignant cell growth and metastasis formation. Most of these newly developed tyrosine kinase inhibitors are hydrophobic and thus rapidly penetrate the cell membrane to reach intracellular targets. However, intracellular accumulation of a drug is regulated by multiple factors, including influx and efflux as well as metabolism. In cancer chemotherapy, overexpression of drug efflux transporters in cancer cells is a major cause of multidrug resistance that reduces the efficacy of anticancer drugs. Thus, the transport mechanism-based molecular design strategy would provide an effective tool for chemotherapy against cancer. To develop a platform for molecular modeling to circumvent multidrug resistance and reduce drug-induced adverse effects, we established methods for high-speed screening for human ABCG2-drug interactions, quantitative structure-activity relationship (QSAR) analysis, and quantum chemical calculation for lead optimization. This review addresses recent advances in the strategy of transport mechanism-based molecular design.