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. 2022 Aug 3;23(15):8635.
doi: 10.3390/ijms23158635.

Identification of Novel Inhibitors Targeting SGK1 via Ensemble-Based Virtual Screening Method, Biological Evaluation and Molecular Dynamics Simulation

Hui Zhang  1 , Chen Shen  1 , Hong-Rui Zhang  1 , Hua-Zhao Qi  1 , Mei-Ling Hu  1 , Qing-Qing Luo  1
Affiliations

Identification of Novel Inhibitors Targeting SGK1 via Ensemble-Based Virtual Screening Method, Biological Evaluation and Molecular Dynamics Simulation

Hui Zhang et al. Int J Mol Sci. .

Abstract

Serum and glucocorticoid-regulated kinase 1 (SGK1), as a serine threonine protein kinase of the AGC family, regulates different enzymes, transcription factors, ion channels, transporters, and cell proliferation and apoptosis. Inhibition of SGK1 is considered as a valuable approach for the treatment of various metabolic diseases. In this investigation, virtual screening methods, including pharmacophore models, Bayesian classifiers, and molecular docking, were combined to discover novel inhibitors of SGK1 from the database with 29,158 compounds. Then, the screened compounds were subjected to ADME/T, PAINS and drug-likeness analysis. Finally, 28 compounds with potential inhibition activity against SGK1 were selected for biological evaluation. The kinase inhibition activity test revealed that among these 28 hits, hit15 exhibited the highest inhibition activity against SGK1, which gave 44.79% inhibition rate at the concentration of 10 µM. In order to further investigate the interaction mechanism of hit15 and SGK1 at simulated physiological conditions, a molecular dynamics simulation was performed. The molecular dynamics simulation demonstrated that hit15 could bind to the active site of SGK1 and form stable interactions with key residues, such as Tyr178, ILE179, and VAL112. The binding free energy of the SGK1-hit15 was -48.90 kJ mol-1. Therefore, the identified hit15 with novel scaffold may be a promising lead compound for development of new SGK1 inhibitors for various diseases treatment.

Keywords: SGK1 inhibitor; biological evaluation; molecular dynamics; virtual screening.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The ensemble-based virtual screening strategy was developed for discovering potent inhibitors targeting for SGK1.
Figure 2
Figure 2
Representative protein conformers based on 3HDM (A) and 3HDN (B) were extracted from the MD trajectory by using structural clustering.
Figure 3
Figure 3
The best pharmacophore models of SGK1 inhibitors. (A) The 3D spatial relationship and geometric parameters of Hypo1. (B) The Hypo1 aligned with cpd1 (IC50 = 0.04 μM). (C) The Hypo1 aligned with lower activity of cpd6 (IC50 = 6.78 μM). (D) The 3D spatial relationship and geometric parameters of Hypo2. (E) The Hypo2 aligned with GMG. (F) The Hypo2 mapped onto the compound with lower activity (IC50 = 2.70 μM).
Figure 4
Figure 4
Distributions of the docking scores of the inhibitors/noninhibitors for each SGK1 protein.
Figure 5
Figure 5
The ROC curve of the naive Bayesian classifier. (A) Training set; (B) test set.
Figure 6
Figure 6
Dynamics of hit15, GMG, and STSP binding to the SGK1 active site. (A) Comparison of orientations of protein backbone for three SGK1-ligand systems. (B) Comparison of orientations of ligands for the three SGK1-ligand systems. (C) Time evolution of radius of gyration (Rg) values during 100 ns MD simulation. (D) Cα atomic fluctuations root-mean-square fluctuation (RMSF) plots. Blue, purple, and red represent the SGK1-hit15, SGK1-GMG, and SGK1-STSP, respectively. Root-mean-square deviation (RMSD) plots as a function of time. (E–G) represented the structural superposition before (blue) and after (green) MD for SGK1-hit15 (E), SGK1-GMG (F), and SGK1-STSP (G). A porcupine plot was generated and the movements of flexible parts of the SGK1 indicated with red arrows, and cone represents the direction.
Figure 7
Figure 7
Molecular dynamics results of SS and SASA during 100 ns MD simulation. (A–C) represented the SS changes during MD simulation for SGK1-hit15 (A), SGK1-GMG (B), and SGK1-STSP (C). (D–F) exhibited the total, hydrophobic, and hydrophilic area changes during MD simulation for SGK1-hit15 (D), SGK1-GMG (E), and SGK1-STSP (F).
Figure 8
Figure 8
Number of hydrogen bond interactions formed during MD simulation in the case of SGK1-hit15 (A), SGK1-GMG (B), and SGK1-STSP (C).
Figure 9
Figure 9
Molecular dynamics results of tertiary contact map for SGK1-STSP (A), SGK1-GMG (B), and SGK1-hit15 (C).
Figure 10
Figure 10
Molecular dynamics results of PCA analysis from the last 5 ns trajectories. Projection of the motion of SGK1-hit15, SGK1-GMG, and SGK1-STSP in phase space along the PC1 and PC2.
Figure 11
Figure 11
Molecular dynamics results of clustering and binding mode analysis. (A) Conformation clustering from the last 3 ns of SGK1-hit15. The Cluster_1 was colored by blue. (B) Conformation clustering from the last 3 ns of SGK1-GMG. The Cluster_1 was colored by purple. (C) Conformation clustering from the last 3 ns of SGK1-STSP. The Cluster_1 was colored by red. (D–F) represents the binding modes of SGK1-hit15 (D), SGK1-GMG (E), and SGK1-STSP (F). Hydrogen bonds are depicted as green dashed lines, Alkyl and Pi-Alkyl are represented as pink dashed lines, Pi-Pi Stacked are depicted as purple-pink dashed lines, Pi-Cation are exhibited as orange dashed lines.
Figure 12
Figure 12
Binding free energy calculated and decomposed by MM/PBSA method. (A) The binding free energies of SGK1-hit15, SGK1-GMG, and SGK1-STSP. (B) The component energies of binding free energy for SGK1-hit15, SGK1-GMG, and SGK1-STSP. (C–E) indicate per-residue binding free-energy decomposition for SGK1-hit15 (C), SGK1-GMG (D), and SGK1-STSP (E). (F) The radar map of 6 important residues binding free-energy decomposition for SGK1-hit15, SGK1-GMG, and SGK1-STSP.
Figure 13
Figure 13
The chemical structures of SGK1 inhibitors together with their biological activity data (IC50) for HipHop running.
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Grants and funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81903543 and 81660589) and Science and Technology Program Project of Gansu Province (20JR5RA534).

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