Title:Benzophenone Sulfonamide Derivatives as Interacting Partners and Inhibitors of Human P-glycoprotein
Volume: 20
Issue: 14
Author(s): Saira Farman, Aneela Javed, Arshia, Khalid M. Khan, Abdul Nasir, Asif Ullah Khan, Muhammad A. Lodhi, Humaira Gul, Faisal Khan, Muhammad Asad and Zahida Parveen*
Affiliation:
- Department of Biochemistry, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa,Pakistan
Keywords:
P-gp, benzophenone sulfonamide, docking, inhibition, ABCB1, MDR.
Abstract:
Background: Human P-glycoprotein (P-gp) is a transmembrane protein that belongs to the ATPBinding
Cassette (ABC) transporters family. Physiologically, it exports toxins out of the cell, however, its overexpression
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 Vcr1000 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
30.66nM±5.49 and 46.12nM±3.06, respectively. Moreover, IC50 values calculated for 14, 11 and 13 in cytotoxicity
assay were found to be 22.97μM±0.026, 583.1μM±0.027 and 117.8μM±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.
