Molecular insights into the behavior of the allosteric and ATP-competitive inhibitors in interaction with AKT1 protein: A molecular dynamics study

Amiran, Mohammad Reza; Taghdir, Majid; Joozdani, Farzane Abasi

doi:10.1016/j.ijbiomac.2023.124853

Cited by 7 publications

(1 citation statement)

References 77 publications

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“…Finally, we observed disparities in how different molecules targeting the same protein impact the target. The library contained two compounds known to target AKT1—MK-2206, an allosteric inhibitor and CCT128930, an ATP- competitive inhibitor (Amiran et al, 2023; Hirai et al, 2010; Yap et al, 2011). Interestingly, engagement of the allosteric ligand, MK-2206, induced a large change in AKT1 thermal stability, while the ATP-competitive inhibitor appeared to have no effect (Figure 1 – figure supplement 4A,B).…”

Section: Resultsmentioning

confidence: 99%

Large-scale characterization of drug mechanism of action using proteome-wide thermal shift assays

Van Vranken,

Li,

Mintseris

et al. 2024

Preprint

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In response to an ever-increasing demand of new small molecules therapeutics, numerous chemical and genetic tools have been developed to interrogate compound mechanism of action. Owing to its ability to characterize compound-dependent changes in thermal stability, the proteome-wide thermal shift assay has emerged as a powerful tool in this arsenal. The most recent iterations have drastically improved the overall efficiency of these assays, providing an opportunity to screen compounds at a previously unprecedented rate. Taking advantage of this advance, we quantified 1.498 million thermal stability measurements in response to multiple classes of therapeutic and tool compounds (96 compounds in living cells and 70 compounds in lysates). When interrogating the dataset as a whole, approximately 80% of compounds (with quantifiable targets) caused a significant change in the thermal stability of an annotated target. There was also a wealth of evidence portending off-target engagement despite the extensive use of the compounds in the laboratory and/or clinic. Finally, the combined application of cell- and lysate-based assays, aided in the classification of primary (direct ligand binding) and secondary (indirect) changes in thermal stability. Overall, this study highlights the value of these assays in the drug development process by affording an unbiased and reliable assessment of compound mechanism of action.

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Section: Resultsmentioning

confidence: 99%

Large-scale characterization of drug mechanism of action using proteome-wide thermal shift assays

Van Vranken,

Li,

Mintseris

et al. 2024

Preprint

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Discovery of natural agents against Staphylococcus aureus based on EIIC by protein modeling, virtual screening and molecular dynamics

Chen,

Li,

Guo

et al. 2024

LWT

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Network Pharmacology, Molecular Docking Analysis and Molecular Dynamics Simulation of Scutellaria baicalensis in the Treatment of Liver Fibrosis

Wang,

Wu,

Chen

et al. 2024

CPD

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Background: Traditional Chinese medicine Scutellaria Baicalensis (SB), one of the clinical firstline heat-clearing drugs, has obvious symptomatic advantages for hepatic fibrosis with dampness-heat stasis as its syndrome. We aim to predict and validate the potential mechanism of Scutellaria baicalensis active ingredients against liver fibrosis more scientifically and effectively. Methods: The underlying mechanism of Scutellaria baicalensis in inhibiting hepatic fibrosis was studied by applying network pharmacology, molecular docking and molecular dynamics simulation. Expression levels of markers in activated Hepatic Stellate Cells (HSC) after administration of three Scutellaria baicalensis extracts were determined by Western blot and Real-time PCR, respectively, in order to verify the anti-fibrosis effect of the active ingredients objective: We aim to predict and validate the potential mechanism of SB active ingredients against liver fibrosis in a more scientific and effective way. Results: There are 164 common targets of drugs and diseases screened and 115 signaling pathways obtained, which were mainly associated with protein phosphorylation, senescence and negative regulation of the apoptotic process. Western blot and Real-time PCR showed that Scutellaria baicalensis extracts could reduce the expression of HSC activation markers, and Oroxylin A had the strongest inhibitory effect on it. Molecular docking results showed that Oroxylin A had high binding activity to target proteins. Molecular dynamics simulation demonstrates promising stability of the Oroxylin A-AKT1 complex over the simulated MD time of 200 ns. Conclusion: Scutellaria baicalensis active ingredients may inhibit HSC proliferation, reduce the generation of pro-inflammatory factors and block the anti-inflammatory effect of inflammatory signal transduction by inducing HSC apoptosis and senescence, thus achieving the effect of anti-fibrosis.

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Molecular insights into the behavior of the allosteric and ATP-competitive inhibitors in interaction with AKT1 protein: A molecular dynamics study

Cited by 7 publications

References 77 publications

Large-scale characterization of drug mechanism of action using proteome-wide thermal shift assays

Large-scale characterization of drug mechanism of action using proteome-wide thermal shift assays

Discovery of natural agents against Staphylococcus aureus based on EIIC by protein modeling, virtual screening and molecular dynamics

Network Pharmacology, Molecular Docking Analysis and Molecular Dynamics Simulation of Scutellaria baicalensis in the Treatment of Liver Fibrosis

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