Design and screening of SGK1, Src dual inhibitors using pharmacophore models, molecular docking, and molecular dynamics simulation

Sun, Chuance; Zhang, Lichuan; Gao, Chenglong; Zhang, Haoran; Yu, Rilei; Kang, Chang‐Hee

doi:10.1039/d0nj02249g

Cited by 3 publications

(2 citation statements)

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“…Dysregulation of SGK1 is a key contributor in cancer − and many other pathological conditions ranging from hypertension, diabetes, and neurodegeneration to thrombotic events. Its expression is highly regulated, making SGK1 an attractive target for specific pharmacologic intervention in a diseased tissue state. − Inhibitors of SGK1 have already been the target of structure-based modeling approaches, and synthetic protein kinase inhibitors have already found use in many neoplastic or inflammatory disease indications, including rheumatoid arthritis . Nevertheless, their application in osteoarthritis is still in its infancy.…”

Section: Introductionmentioning

confidence: 99%

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Rational Design of Highly Potent, Selective, and Bioavailable SGK1 Protein Kinase Inhibitors for the Treatment of Osteoarthritis

et al. 2021

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The serine/threonine kinase SGK1 is an activator of the β-catenin pathway and a powerful stimulator of cartilage degradation that is found to be upregulated under genomic control in diseased osteoarthritic cartilage. Today, no oral diseasemodifying treatments are available and chronic treatment in this indication sets high requirements for the drug selectivity, pharmacokinetic, and safety profile. We describe the identification of a highly selective druglike 1H-pyrazolo[3,4-d]pyrimidine SGK1 inhibitor 17a that matches both safety and pharmacokinetic requirements for oral dosing. Rational compound design was facilitated by a novel hSGK1 co-crystal structure, and multiple ligandbased computer models were applied to guide the chemical optimization of the compound ADMET and selectivity profiles. Compounds were selected for subchronic proof of mechanism studies in the mouse femoral head cartilage explant model, and compound 17a emerged as a druglike SGK1 inhibitor, with a highly optimized profile suitable for oral dosing as a novel, potentially disease-modifying agent for osteoarthritis.

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Section: Introductionmentioning

confidence: 99%

“…h i b i t e d .N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,3-dichloro-benzenesulfonamide Trifluoroacetate 1.1 H NMR (DMSOd 6 ) δ 7.27 (d, J = 8.8 Hz, 2H), 7.58 (t, J = 8.1 Hz, 1H), 7.94 (dd, J = 1.4, 8.0 Hz, 2H), 8.07 (d, J = 8.8 Hz, 2H), 8.12 (dd, J = 1.4, 8.0 Hz, 2H), 8.89 (s, 1H), 11 15. (s, 1H); MS (ES+) calcd for [M + H] 435.02, found 435.03.…”

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confidence: 99%

Rational Design of Highly Potent, Selective, and Bioavailable SGK1 Protein Kinase Inhibitors for the Treatment of Osteoarthritis

et al. 2021

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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

Verma

Ahmed

Hossain

et al. 2021

Journal of Biomolecular Structure and Dynamics

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Discovery of novel CDK2 inhibitors for cancer treatment: integrating ligand-based pharmacophore modelling, molecular docking, DFT, ADMET, and molecular dynamics simulation studies

Chagaleti,

Saravanan,

Kathiravan

2024

Beni-Suef Univ J Basic Appl Sci

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Background The global landscape of public health faces significant challenges attributed to the prevalence of cancer and the emergence of treatment resistance. This study addresses these challenges by focusing on Cyclin-dependent Kinase 2 (CDK2) and employing a systematic computational approach for the discovery of novel cancer therapeutics. Results Initial ligand-based pharmacophore modelling, utilizing a training set of five reported CDK2 inhibitors, yielded a robust model characterized by Aro|Hyd| and |Acc|Don| features. Screening this validated model against the ZINC database identified 1881 hits, which were further subjected to molecular docking studies. The top 10 compounds (Z1–Z10) selected from the docking studies underwent Pharmacokinetic parameters Absorption, Distribution, Metabolism, Excretion and Toxicity profiling, Density Functional Theory (DFT) studies and the top two went for 100ns molecular dynamics (MD) simulations by comparing them with the standard Roscovitine. Compounds Z1 and Z2 emerged as the most promising, with docking scores of − 8.05 kcal/mol and − 8.02 kcal/mol, respectively. DFT analysis of the top 10 compounds revealed minimal variations in highest occupied molecular orbital–lowest unoccupied molecular orbital energy gaps, indicating consistent electronic stability and reactivity across the candidates. MD simulations of Z1 and Z2 confirmed their stable interactions with CDK2, with root mean square deviation (RMSD) values ranging from 1.4 to 2.5 Å for Z1 and 1.5 to 2.4 Å for Z2. Conclusion The current research identified compounds Z1 and Z2, which demonstrated significant potential as potent CDK2 inhibitors for cancer therapy, providing valuable insights into the development of more effective CDK2 inhibitors and addressing the critical need for innovative therapeutic strategies in cancer treatment. Graphical abstract

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Design and screening of SGK1, Src dual inhibitors using pharmacophore models, molecular docking, and molecular dynamics simulation

Abstract: Serum and glucocorticoid-regulated protein kinase 1 (SGK1) is highly expressed in many tumors that can promote the growth of tumor cells. Sarcoma gene (Src) is a class of oncogenes, plays...

Cited by 3 publications

References 23 publications

Rational Design of Highly Potent, Selective, and Bioavailable SGK1 Protein Kinase Inhibitors for the Treatment of Osteoarthritis

Rational Design of Highly Potent, Selective, and Bioavailable SGK1 Protein Kinase Inhibitors for the Treatment of Osteoarthritis

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

Discovery of novel CDK2 inhibitors for cancer treatment: integrating ligand-based pharmacophore modelling, molecular docking, DFT, ADMET, and molecular dynamics simulation studies

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