Structure-Activity Relationships of Multidrug Resistance Reversers

Abstract

Multidrug resistance, MDR, is a major obstacle in the chemotherapeutic treatment of cancer. MDR can be reversed by drugs that vary widely in their chemical structure and main biological action. Many efforts are directed to find out the relationships between the structure and MDR reversal effect of these drugs. In this review we try to summarize the results of a variety of studies on identification of structure-activity relationships, SARs, and quantitative SARs, QSARs, of different MDR reversing drugs. As any reasonable (Q)SAR study relies on a real or putative presentation about the mechanism of action of the studied compounds, the most significant MDR mechanisms revealed till now are shortly discussed. Special attention is paid to P-glycoprotein, P-gp, related MDR as the most experimentally and clinically tested form of drug resistance. The currently proposed models of P-gp functioning and mechanisms of MDR modulation are presented. Problems that can arise in (Q)SARs studies are discussed in advance to allow the reader to judge on possible pitfalls. The physicochemical and structural properties of MDR modulators as found by different research groups are commented and summarized. From the discussed studies it can be concluded that the careful selection of relevant structural and biological data processed with appropriate QSAR and especially 3D-QSAR methods, is a promising approach to structure-activity studies of MDR reversers.

Proteomics Analysis of Ovarian Cancer Cell Lines and Tissues Reveals Drug Resistance-associated Proteins

“…Approaches to overcoming taxane resistance include the use of multidrug resistance modulators (13), if the resistance correlates with p-glycoprotein (P-gp) overexpression, or novel cytotoxic molecules, developed on the basis of activity in Taxol-resistant models, such as the epothilones (14), although these approaches have had limited success in clinical trials (15).…”

4-Hydroxy-6-methoxyaurones with High-Affinity Binding to Cytosolic Domain of P-Glycoprotein.

“…6) During the past decade, a tremendous effort has been made to find compounds which are able to overcome MDR by restoring the intracellular accumulation of antitumor agents in resistant cells. 7,8) Our group, has investigated the field of flavonoids which interact with the C-terminal nucleotide-binding domain of P-glycoprotein and may constitute potential MDR modulators. We have studied flavones, flavonols, chalcones and other phenolic compounds, and have identified the structural criteria required for a high binding-affinity.…”

Recent Development and Application of Virtual Screening in Drug Discovery: An Overview

“…QSAR and pharmacophore modeling were applied to study the common features of p-gp substrate, the interactions between substrate and P-gp [156][157][158][159][160][161]. On the basis of the obtained results, we can give some explanations to the broad structural variety of the P-gp substrates and inhibitors and give predicted models for discrimination between substrate and non-substrate, but at present the accuracy of those models is too limited to be applied in virtual screening.…”