Discovery of GSK3β Inhibitors through In Silico Prediction-and-Experiment Cycling Strategy, and Biological Evaluation
Abstract
:1. Introduction
2. Results and Discussions
2.1. Molecular Dynamics (MD) Simulation of Reference Compound, SB216763, with GSK3β
2.2. Virtual Screening
2.3. HTS Campaign and Following In Vitro Enzyme Assays
2.4. Binding Mode Analyses of Hit Compound Cpd1
2.5. Molecular Docking Study for the Hit Derivatives
2.6. Wnt Signaling Activity Study for the Active Compounds
2.7. Discussions for Molecular Modeling Approaches
3. Materials and Methods
3.1. Molecular Docking Simulation
3.2. Molecular Dynamics (MD) Simulation
3.3. Pharmacophore Model Generation and Virtual Screening
3.4. High-Throughput Screening (HTS) of GSK3β Kinase Assay (TR-FRET)
3.5. Reversibility Assay
3.6. Reporter Assay
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Serial Number | R1 | R2 | GSK3β Kinase Assay | |
---|---|---|---|---|
%Inhibition (0.5 μM/5 μM) | IC50 (nM) | |||
1 | 100/100 | 37 ± 6 | ||
2 | 78/100 | 211 ± 55 | ||
3 | Et | 57/98 | 379 ± 50 | |
4 | 57/96 | 347 ± 56 | ||
5 | 38/95 | 701 ± 118 | ||
6 | Et | 45/91 | 730 ± 113 | |
7 | CH3 | 30/90 | 1027 ± 66 | |
8 (SB216763) | 61/100 | 35 ± 12 |
Compound | IC50 (nM) | Glide_Evdw | Glide_Ecoul | Glide_Energy | Glide_XP_Hbond | CIE | CE |
---|---|---|---|---|---|---|---|
1 | 40 | −43.94 | −7.05 | −50.99 | −1.08 | 45.67 | 21.48 |
2 | 254 | −40.66 | −7.07 | −47.73 | −0.35 | 41.11 | 10.56 |
3 | 334 | −33.39 | −7.56 | −40.95 | −0.97 | 33.25 | 8.16 |
4 | 485 | −39.62 | −2.47 | −42.09 | −0.31 | 34.49 | −56.24 |
5 | 776 | −30.95 | −4.09 | −35.04 | −0.40 | 39.27 | −3.75 |
6 | 1166 | −40.90 | −2.14 | −43.04 | −0.03 | 34.04 | 10.12 |
7 | 1190 | −33.86 | −3.85 | −37.71 | 0 | 33.13 | 13.95 |
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Lee, Y.; Yoon, S.-B.; Hong, H.; Kim, H.Y.; Jung, D.; Moon, B.-S.; Park, W.-K.; Lee, S.; Kwon, H.; Park, J.; et al. Discovery of GSK3β Inhibitors through In Silico Prediction-and-Experiment Cycling Strategy, and Biological Evaluation. Molecules 2022, 27, 3825. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27123825
Lee Y, Yoon S-B, Hong H, Kim HY, Jung D, Moon B-S, Park W-K, Lee S, Kwon H, Park J, et al. Discovery of GSK3β Inhibitors through In Silico Prediction-and-Experiment Cycling Strategy, and Biological Evaluation. Molecules. 2022; 27(12):3825. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27123825
Chicago/Turabian StyleLee, Yuno, Sae-Bom Yoon, Hyowon Hong, Hyun Young Kim, Daeyoung Jung, Byoung-San Moon, Woo-Kyu Park, Sunkyung Lee, Hyukjin Kwon, Jihyeong Park, and et al. 2022. "Discovery of GSK3β Inhibitors through In Silico Prediction-and-Experiment Cycling Strategy, and Biological Evaluation" Molecules 27, no. 12: 3825. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27123825