Pharmacophore-Based Virtual Screening of Novel GSTP1-1 Inhibitors

Year 2018, Volume: 5 Issue: 3, 1279 - 1286, 01.09.2018

Kayhan Bolelli , Tugba Ertan-bolelli

https://doi.org/10.18596/jotcsa.466458

Cited By: 1

Abstract

Glutathione
transferase enzymes play an important role in metabolism and detoxification of
numerous xenobiotics, electrophilic drugs, environmental carcinogens, and
products of oxidative stress in living organisms.
Human GST P1-1 is the most prevalent
isoform of the mammalian cytosolic GSTs and this enzyme participates in a
particular role in one of the mechanisms of the development of resistance in
cancer cells toward the administration of anticancer agents in chemotherapy.

Herein,
pharmacophore analysis were performed using bioactive conformation of the known
inhibitor of GSTP1-1, ethacrynic acid (pdb ID:2GSS). Phase module of the
Schrödinger suite was used to generate pharmacophore hypothesis. Molecules with
same pharmacophoric features were screened from among the commercially
available compounds in the ZINC database and ligand filtration was also done to
obtain an efficient collection of hit molecules by employing Lipinski “rule of
five” using Qikprop module. As a result, some of the compounds obtained from
this study, could be the promising inhibitors of hGSTP1-1 enzyme.

Keywords

ADME/Tox, drug resistance, GSTP1-1, pharmacophore analysis, virtual screening

References

• 1. Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Ann Rev Pharmacol Toxicol. 2005; 45:51–88.
• 2. Commandeur JNM, Stijntjes GJ, Vermeulen NPE. Enzymes and transport-systems involved in the formation and disposition of glutathione S-conjugates—Role in bioactivation and detoxication mechanisms of xenobiotics. Pharmacol Rev. 1995; 47:271–330.
• 3. Josephy PD, Mannervik B. Molecular toxicology. 2nd ed. New York (NY): Oxford University Press; 2006.
• 4. Kazemnejad S, Rasmi Y, Sharifi R, Allameh A. Class-Pi of glutathione S transferases. Iran J Biotechnol. 2006; 4(1):1–16.
• 5. Sau A, Tregno FP, Valentino F, Federici G, Caccuri AM. Glutathione transferases and development of new principles to overcome drug resistance. Arch Biochem Biophys 2010; 500(2):116-22.
• 6. Kong KH, Takasu K, Inoue H, Takahashi K. Tyrosine-7 in human class-Pi glutathione-S-transferase is important for lowering the pka of the thiol-group of glutathione in the enzyme-glutathione complex. Biochem Biophys Res Commun. 1992; 184:194–7.
• 7. Tew KD, Dutta S, Schultz M. Inhibitors of glutathione S-transferases as therapeutic agents. Adv Drug Deliv Rev. 1997; 26(2-3):91-104.
• 8. Mathew N, Kalyanasundaram M, Balaraman K. Glutathione S-transferase (GST) inhibitors. Expert Opin Ther Pat. 2006; 16:431–44.
• 9. DePierre J, Morgenstern R. Comparison of the distribution of microsomal and cytosolic glutathione S-transferase activities in different organs of the rat. Biochem Pharmacol. 1983; 32:721–3.
• 10. Van Bladeren PJ. Glutathione conjugation as a bioactivation reaction. Chem Biol Interact. 2000; 129:61–76.
• 11. Guner OF. Pharmacophore perception, development, and use in drug design. Int Univ Line. 2000.
• 12. Mason JS, Good AC, Martin EJ. 3-D pharmacophores in drug discovery. Curr Pharm Des. 2001; 7(7):567–97.
• 13. Leach AR, Gillet VJ, Lewis RA, Taylor R. Three-dimensional pharmacophore methods in drug discovery. J Med Chem. 2010; 53(2):539–58.
• 14. Langer T, Hoffmann RD. Pharmacophores and Pharmacophore Searches. Wiley-VCH, 2006.
• 15. Diniz EMLP, Poiani JGC, Taft CA, da Silva CHTP. Structure-Based Drug Design, Molecular Dynamics and ADME/Tox to Investigate Protein Kinase Anti-Cancer Agents. Curr Bioact Comp. 2017; 13(3):213–22.
• 16. Kaserer T, Beck KR, Akram M, Odermatt A, Schuster D. Pharmacophore Models and Pharmacophore-Based Virtual Screening: Concepts and Application Exemplified on Hydroxysteroid Dehydrogenases. Molecules. 2015; 20:22799–832.
• 17. Rohini K, Shanthi V. Discovery of Potent Neuraminidase Inhibitors Using a Combination of Pharmacophore-Based Virtual Screening and Molecular Simulation Approach. Appl Biochem Biotechnol. 2018; 184:1421–40.
• 18. Schrödinger Release 2018-2: Phase, Schrödinger, LLC, New York, NY, 2018.
• 19. Schrödinger Release 2018-2: QikProp, Schrödinger, LLC, New York, NY, 2018.
• 20. Oakley AJ, Rossjohn J, Lo Bello M, Caccuri AM, Federici G, Parker MW. The three-dimensional structure of the human Pi class glutathione transferase P1-1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate. Biochemistry. 1997; 36:576-85.
• 21. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2012; 64(1‑3):4‑17.