Unlocking SGK1 inhibitor potential of bis-[1-N,7-N, pyrazolo tetraethoxyphthalimido{-4-(3,5-Dimethyl-4-(spiro-3-methylpyazolo)-1,7-dihydro-1H-dipyrazolo[3,4-b;4',3'-e]pyridin-8-yl)}]p-disubstituted phenyl compounds: a computational study

Abstract

SGK1 (Serum and Glucocorticoid Regulated Kinase 1), a serine/threonine kinase that is activated by various stimuli, including serum and glucocorticoids. It controls inflammation, apoptosis, hormone release, neuro-excitability and cell proliferation, all of which play an important role in cancer progression and metastasis. SGK1 was recently proposed as a potential drug target for cancer, diabetes, and neurodegenerative diseases. In this study, molecular docking, physiochemical, toxicological properties and molecular dynamic simulation of the Bis-[1-N,7-N, Pyrazolo tetraethoxyphthalimido{-4-(3,5-Dimethyl-4-(spiro-3-methylpyazolo)-1,7-dihydro-1H-dipyrazolo[3,4-b;4',3'-e]pyridin-8-yl)}]p-disubstituted phenyl compoundsand reference EMD638683 against new SGK1 target protein. Compared to the reference inhibitor EMD638683, we choose the best compounds (series 2-6) based on the binding energy (in the range from −11.0 to −10.6 kcal/mol). With the exception of compounds 2 and 6, none of the compounds posed a risk for AMES toxicity or carcinogenicity due to their toxicological properties. 100 ns MD simulation accompanied by MM/PBSA energy calculations and PCA. According to MD simulation results, the binding of compounds 3, 4 and 5 stabilizes the SGK1 structure and causes febrile conformational changes compared to EMD638683. As a result of this research, the final selected compounds 3, 4 and 5 can be used as scaffolds to develop promising SGK1 inhibitors for the treatment of related diseases such as cancer.

Communicated by Ramaswamy H. Sarma

Graphical Abstract

Highlights

• Bis-[1-N,7-N,Pyrazolotetraethoxyphthalimido{-4-(3,5-Dimethyl-4-(spiro-3-methylpyazolo)-1,7-dihydro-1H-dipyrazolo[3,4-b;4',3'-e]pyridin-8-yl)}]p-disubstituted phenyl compounds bind to the SGK1 protein.

• In Comparison to reference inhibitor EMD638683, compound (2-6) have strong binding affinities and interactions with SGK1 protein complexes.

• The RMSD, RMSF, Radius of gyration, Residual correlative motion (RCM), No. of hydrogen bonds, Protein secondary structure content, Per-residue protein secondary structure, and MM/PBSA energy and PCA calculated for selected compound 3, 4, and 5 compare to control EMD638683 through MD simulation studies for 100ns.

Keywords:

• Serum/glucocorticoid-regulated kinase 1
• molecular docking
• MM/PBSA
• molecular dynamics simulation
• cancer
• synthetic compounds

Authors contributions

Conceptualization A.K.V.; Methodology A.K.V.; Software A.K.V., M.S.H., S.F.A., Md.MR, and NMB; Validation A.K.V., M.S.H., and S.F.A.; Formal analysis A.K.V. and S.F.A.; Investigation A.K.V.; Resources A.K.V. M.S.H. and S.F.A.; Data curation AKV. Writing-original draft preparation A.K.V.; Writing-review and editing A.A.B., A.K.S., and S.K.U., N.S., H; Visualization A.K.V. All authors have read and agreed to the published version of the manuscript.

Acknowledgements

The authors are thankful to Dr. Ashok kumar Gadiya, Chairman Mewar University, Gangrar, Rajasthan for his continues support and assistance throughout the work. Department of Life Sciences, Faculty of Science & Technology, and Mewar University for providing necessary infrastructure facilities. AKV acknowledges the Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University for conducting MD Simulation. SKU and NS are thankful to the Department of Environmental Science and Department of Pharmacy, V.B.S. Purvanchal University.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that have appeared to influence the work reported in this manuscript.

Additional information

Funding

This research received no external funding.