Abstract
Background: Human P-glycoprotein (P-gp) is a transmembrane protein that belongs to the ATP-Binding Cassette (ABC) transporters family. Physiologically, it exports toxins out of the cell, however, its over-expression leads to the phenomena of Multidrug-Resistance (MDR) by exporting a diverse range of compounds, which are structurally and chemically different from each other, thus creating a hurdle in the treatment of various diseases including cancer. The current study was designed to screen benzophenone sulfonamide derivatives as a class of inhibitors and potential anticancer agents for P-gp.
Methods: A total number of 15 compounds were evaluated. These compounds were screened in daunorubicin efflux inhibition assays using CCRF-CEM Vcr(1000) cell line that overexpressed human P-gp. Cytotoxicity assay was also performed for active compounds 11, 14, and 13. These scaffolds were then docked in the homology model of human P-gp using mouse P-gp as a template (PDB ID: 4MIM) and the recently published Cryo Electron Microscopy (CEM) structure of human mouse chimeric P-gp to find their interactions with specified residues in the binding pocket. Analysis was performed using Labview VI and Graph pad prism version 5.0.
Results: Results revealed the potency of all these compounds in low nanomolar range whereas, compound 14 was found to be most active with IC50 value of 18.35nM +/- 4.90 followed by 11 and 13 having IC50 values of 30.66nM5.49 and 46.12nM3.06, respectively. Moreover, IC50 values calculated for 14, 11 and 13 in cytotoicity assay were found to be 22.97 mu M +/- 0.026, 583.1 mu M +/- 0.027 and 117.8 mu M +/- 0.062, respectively. Docking results showed the interaction of these scaffolds in transmembrane helices (TM) where Tyr307, Tyr310, Tyr953, Met986 and Gln946 were found to be the major interaction partners, thus they might play a significant role in the transport of these scaffolds.
Conclusion: Benzophenone sulfonamide derivatives showed IC50 values in low nanomolar range comparable to the standard inhibitor Verapamil, therefore they can be good inhibitors of P-gp and can serve as anticancer agents. Also, they have shown interactions in the transmembrane region sharing the same binding region of verapamil and zosuquidar.