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
Creators: name: Verma, Abhishek Kumar
name: Ahmed, Sk. Faisal
name: Hossain, Md.Shahadat
name: Bhojiya, Ali Asger
name: Upadhyay, Sudhir K.
name: Srivastava, Abhishek K.
name: Singh, Nripendra
name: Harina
name: Rahaman, Md. Mizanur
name: Bahadur, Newaz Mohammed
Publisher: name: Taylor & Francis
Year: 2021
Subjects: subject: Biophysics
subject: Biochemistry
subject: Pharmacology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: FOS: Biological sciences
subject: Cancer

description: 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. 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. 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. Communicated by Ramaswamy H. Sarma