Virtual Screening Approach to Identify High-Affinity Inhibitors of Serum and Glucocorticoid-Regulated Kinase 1 among Bioactive Natural Products: Combined Molecular Docking and Simulation Studies

Mohammad, Taj; Siddiqui, Shiza; Shamsi, Anas; Alajmi, Mohamed F.; Hussain, Afzal; Islam, Asimul; Ahmad, Faizan; Hassan, Md. Imtaiyaz

doi:10.3390/molecules25040823

Cited by 117 publications

(63 citation statements)

References 60 publications

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“…In light of the emerging evidence highlighting multiple roles for SGK1 in mediating tumorigenesis and progression, several specific and selective inhibitors of SGK1 have been developed, including GSK650394 ( 49 ), EMD638683 ( 140 ), SI113 ( 141 ), QGY-5-114-A ( 72 ), and ZINC00319000 ( 142 ). The mentioned SGK1 inhibitors and their various anti-tumor effects are summarized in Table 2 .…”

Section: Sgk1 Inhibitorsmentioning

confidence: 99%

“…Using a structure-based virtual high-throughput screening strategy, Mohammad et al ( 142 ) found four compounds bearing appreciable binding affinity and specificity towards the binding pocket of SGK1. Among them, the compound ZINC00319000 was selected and identified based on docking results with all-atom molecular dynamics simulation for 100 ns.…”

Section: Sgk1 Inhibitorsmentioning

confidence: 99%

“…Among them, the compound ZINC00319000 was selected and identified based on docking results with all-atom molecular dynamics simulation for 100 ns. Molecular dynamics simulation results further suggested that the binding of ZINC00319000 stabilizes the SGK1 structure and leads to few conformational changes, indicating that ZINC00319000 might be further exploited as a scaffold to develop promising inhibitors of SGK1 for therapeutic management of associated diseases, including cancer ( 142 ). However, its anti-tumor effects and mechanisms need to be further investigated.…”

Section: Sgk1 Inhibitorsmentioning

confidence: 99%

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SGK1 in Human Cancer: Emerging Roles and Mechanisms

et al. 2021

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Serum and glucocorticoid-induced protein kinase 1 (SGK1) is a member of the “AGC” subfamily of protein kinases, which shares structural and functional similarities with the AKT family of kinases and displays serine/threonine kinase activity. Aberrant expression of SGK1 has profound cellular consequences and is closely correlated with human cancer. SGK1 is considered a canonical factor affecting the expression and signal transduction of multiple genes involved in the genesis and development of many human cancers. Abnormal expression of SGK1 has been found in tissue and may hopefully become a useful indicator of cancer progression. In addition, SGK1 acts as a prognostic factor for cancer patient survival. This review systematically summarizes and discusses the role of SGK1 as a diagnostic and prognostic biomarker of diverse cancer types; focuses on its essential roles and functions in tumorigenesis, cancer cell proliferation, apoptosis, invasion, metastasis, autophagy, metabolism, and therapy resistance and in the tumor microenvironment; and finally summarizes the current understanding of the regulatory mechanisms of SGK1 at the molecular level. Taken together, this evidence highlights the crucial role of SGK1 in tumorigenesis and cancer progression, revealing why it has emerged as a potential target for cancer therapy.

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Section: Sgk1 Inhibitorsmentioning

confidence: 99%

Section: Sgk1 Inhibitorsmentioning

confidence: 99%

Section: Sgk1 Inhibitorsmentioning

confidence: 99%

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SGK1 in Human Cancer: Emerging Roles and Mechanisms

et al. 2021

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“…In addition, Poisson-Boltzmann surface area continuum solvation (MM/PBSA) (Fu et al, 2018;Hu et al, 2017;Kumari et al, 2014;Moesgaard et al, 2020;Xue et al, 2018) was also performed to calculate the free binding energy of the ligand. Distance of 3.2 Å was kept as cutoff for bond length for salt bridge and hydrogen bond interactions (Mohammad et al, 2020;. All graphical presentation was prepared using Origin 6.0.…”

Section: Simulations Analysismentioning

confidence: 99%

Identification of potential inhibitors of SARS-COV-2 endoribonuclease (EndoU) from FDA approved drugs: a drug repurposing approach to find therapeutics for COVID-19

Chandra

Gurjar²,

Qamar

et al. 2020

Journal of Biomolecular Structure and Dynamics

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SARS-CoV-2 is causative agent of COVID-19, which is responsible for severe social and economic disruption globally. Lack of vaccine or antiviral drug with clinical efficacy suggested that drug repurposing approach may provide a quick therapeutic solution to COVID-19. Nonstructural protein-15 (NSP15) encodes for an uridylate-specific endoribonuclease (EndoU) enzyme, essential for virus life cycle and an attractive target for drug development. We have performed in silico based virtual screening of FDA approved compounds targeting EndoU in search of COVID-19 drugs from commercially available approved molecules. Two drugs Glisoxepide and Idarubicin used for treatment for diabetes and leukemia, respectively, were selected as stronger binder of EndoU. Both the drugs bound to the active site of the viral endonuclease by forming attractive intermolecular interactions with catalytically essential amino acid residues, His235, His250, and Lys290. Molecular dynamics simulation studies showed stable conformation dynamics upon drugs binding to endoU. The binding free energies for Glisoxepide and Idarubicin were calculated to be-141 ± 11 and-136 ± 16 kJ/mol, respectively. The IC 50 were predicted to be 9.2 mM and 30 mM for Glisoxepide and Idarubicin, respectively. Comparative structural analysis showed the stronger binding of EndoU to Glisoxepide and Idarubicin than to uridine monophosphate (UMP). Surface area calculations showed buried are of 361.8Å 2 by Glisoxepide which is almost double of the area occupied by UMP suggesting stronger binding of the drug than the ribonucleotide. However, further studies on these drugs for evaluation of their clinical efficacy and dose formulations may be required, which may provide a quick therapeutic option to treat COVID-19.

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“…Generally, a protein molecule achieves its function through the collective motion of its atoms, and therefore these atomic motions are widely used to assess the conformational stability of protein-ligand complexes (Mohammad et al, 2020). PCA was performed to reveal the essential and biologically relevant motions from the global trajectories of NSP15 and its drug bound complexes.…”

Section: Principal Component Analysis (Pca)mentioning

confidence: 99%

Identification of promising antiviral drug candidates against non-structural protein 15 (NSP15) from SARS-CoV-2: anin silicoassisted drug-repurposing study

Khan

Jha

Singh

et al. 2020

Journal of Biomolecular Structure and Dynamics

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The recent COVID-19 pandemic caused by SARS-CoV-2 has recorded a high number of infected people across the globe. The virulent nature of the virus makes it necessary for us to identify promising therapeutic agents in a time-sensitive manner. The current study utilises an in silico based drug repurposing approach to identify potential anti-viral drug candidates targeting non-structural protein 15 (NSP15), i.e. a uridylate specific endoribonuclease of SARS-CoV-2 which plays an indispensable role in RNA processing and viral immune evasion from the host immune system. The NSP15 protein was screened against an in-house library of 123 antiviral drugs obtained from the DrugBank database from which three promising drug candidates were identified based on their estimated binding affinities (DG), estimated inhibition constants (Ki), the orientation of drug molecules in the active site and the key interacting residues of NSP15. Molecular dynamics (MD) simulations were performed for the screened drug candidates in complex with NSP15 as well as the apo form of NSP15 to mimic their physiological states. Based on the stable MD simulation trajectories, the binding free energies of the screened NSP15-drug complexes were calculated using the MM/PBSA approach. Two candidate drugs, Simeprevir and Paritaprevir, achieved the lowest binding free energies for NSP15, with a value of À259.522 ± 17.579 and À154.051 ± 33.628 kJ/mol, respectively. In addition, their complexes with NSP15 also exhibited the strongest structural stabilities. Taken together, we propose that Simeprevir and Paritaprevir are promising drug candidates to inhibit NSP15 and may act as potential therapeutic agents against SARS-CoV-2.

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Virtual Screening Approach to Identify High-Affinity Inhibitors of Serum and Glucocorticoid-Regulated Kinase 1 among Bioactive Natural Products: Combined Molecular Docking and Simulation Studies

Cited by 117 publications

References 60 publications

SGK1 in Human Cancer: Emerging Roles and Mechanisms

SGK1 in Human Cancer: Emerging Roles and Mechanisms

Identification of potential inhibitors of SARS-COV-2 endoribonuclease (EndoU) from FDA approved drugs: a drug repurposing approach to find therapeutics for COVID-19

Identification of promising antiviral drug candidates against non-structural protein 15 (NSP15) from SARS-CoV-2: anin silicoassisted drug-repurposing study

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