3D Pharmacophore-Based Discovery of Novel KV10.1 Inhibitors with Antiproliferative Activity
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Virtual Compound Library Preparation
2.2. Ligand-Based Pharmacophore Modelling
2.3. Virtual Screening
2.4. Chemistry
2.5. Electrophysiological Recordings
2.6. Statistical Analysis
2.7. Cell Culture
2.8. Evaluation of Mutagenic Activity with Salmonella/Microsomal Reverse Mutation Assay
3. Results
3.1. Ligand-Based Identification of Novel KV10.1 Inhibitors through in Silico Screening
3.2. Patch-Clamp Screening of Virtual Screening Hit Compounds
3.3. Characterisation of the KV10.1 Inhibition by ZVS-08
3.4. Analogues of the Hit Compound ZVS-08 and Structure–Activity Relationships
3.5. Selectivity of Compounds ZVS-08 and 1 against Other Voltage-Gated Ion Channels
3.6. Effects on the Growth of Cell Lines in 2D Cell Culture
3.7. 3D Cell Based Assays
3.8. Mutagenic Activity of ZVS-08 and 8
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound ID | Structure | Pharmacophore Fit Score | Effect on Kv10.1 (% Inhibition) |
---|---|---|---|
ZVS-01 | 66.4900 | −1.13 ± 4.50 (3) | |
ZVS-02 | 66.4745 | 5.03 ± 2.87 (3) | |
ZVS-03 | 66.4421 | −1.14 ± 3.47 (5) | |
ZVS-04 | 66.0596 | −0.86 ± 0.75 (5) | |
ZVS-05 | 65.9545 | 8.84 ± 4.92 (6) | |
ZVS-06 | 65.8501 | −7.50 ± 4.65 (4) | |
ZVS-07 | 65.8019 | 4.68 ± 1.63 (5) | |
ZVS-08 | 65.7908 | 80.27 ± 0.63 (3) | |
ZVS-09 | 65.1035 | 0.15 ± 1.67 (4) |
Compound ID | IC50 Kv10.1 (μM) | IC50 hERG (μM) |
---|---|---|
ZVS-08 | 3.70 µM (95% CI: 2.08 µM to 6.47 µM) | 0.194 µM (95% CI: 0.047 µM to 0.761 µM) |
1 | 0.740 µM (95% CI: 490 nM to 1.17 µM) | 0.207 µM (95% CI: 0.113 µM to 0.395 µM) |
8 | 1.01 µM (95% CI: 796 nM to 1.30 µM | 0.156 µM (95% CI: 0.070 µM to 0.373 µM) |
Compound ID | Structure | % of Kv10.1 Inhibition at 10 μM |
---|---|---|
1 | 87.32 ± 4.60 (7) | |
2 | 23.93 ± 26.80 (4) | |
3 | 22.08 ± 33.52 (4) | |
4 | 36.63 ± 19.89 (7) | |
5 | 2.53 ± 11.73 (3) | |
6 | 57.48 ± 28.38 (3) | |
7 | 20.96 ± 30.27 (7) | |
8 | 81.20 ± 4.97 (3) | |
9 | 2.00 ± 7.45 (4) | |
10 | 57.05 ± 21.71 (2) | |
11 | 37.67 ± 7.13 (2) | |
12 | 16.60 ± 38.36 (2) |
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Toplak, Ž.; Hendrickx, L.A.; Gubič, Š.; Možina, Š.; Žegura, B.; Štern, A.; Novak, M.; Shi, X.; Peigneur, S.; Tytgat, J.; et al. 3D Pharmacophore-Based Discovery of Novel KV10.1 Inhibitors with Antiproliferative Activity. Cancers 2021, 13, 1244. https://doi.org/10.3390/cancers13061244
Toplak Ž, Hendrickx LA, Gubič Š, Možina Š, Žegura B, Štern A, Novak M, Shi X, Peigneur S, Tytgat J, et al. 3D Pharmacophore-Based Discovery of Novel KV10.1 Inhibitors with Antiproliferative Activity. Cancers. 2021; 13(6):1244. https://doi.org/10.3390/cancers13061244
Chicago/Turabian StyleToplak, Žan, Louise Antonia Hendrickx, Špela Gubič, Štefan Možina, Bojana Žegura, Alja Štern, Matjaž Novak, Xiaoyi Shi, Steve Peigneur, Jan Tytgat, and et al. 2021. "3D Pharmacophore-Based Discovery of Novel KV10.1 Inhibitors with Antiproliferative Activity" Cancers 13, no. 6: 1244. https://doi.org/10.3390/cancers13061244