Identification of Potential Dual HDAC6 and HSP90 Inhibitors for the Treatment of Cancer using Molecular Docking,
Muhsin Samet Yücel1, İsmail Akçok2
1Bioengineering Department, Graduate School of Engineering and Science, Abdullah Gül University, Kayseri, Turkiye.
Background:
Histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90) are crucial therapeutic targets in cancer research with their interconnected roles in regulating protein homeostasis and cellular processes. The interaction of these proteins within the cytosolic complex plays a critical role in regulating cancer cell survival and progression. Notably, current studies highlight that the simultaneous inhibition of HDAC6 and Hsp90 can produce synergistic effects and offer a promising therapeutic potential for combating malignant cancers.
Objective:
The objective of this study was to explore potential compounds that can inhibit both HDAC6 and Hsp90 proteins.
Methods:
In this study, a number of in-silico computational techniques were employed. A total of 791 molecules, sharing at least 30% similarity with previously identified four HDAC inhibitors, were obtained from the ZINC15 database and subjected to docking on HDAC6 and Hsp90 proteins. The top eight ligands demonstrating the best binding scores against both targets, with panobinostat and ganetespib serving as reference compounds for HDAC6 and Hsp90, respectively, were selected for further analysis. Subsequently, ADME prediction and molecular dynamics simulations were conducted on the selected ligands.
Results:
A detailed molecular docking, molecular dynamics simulations and ADME studies have revealed that ZINC27653366 exhibited the highest inhibitory potential against both Hsp90 and HDAC6 target proteins, making it the most promising inhibitor.
Conclusion:
In conclusion, although additional in vitro and in vivo studies are required for the validation, in silico evaluation of ZINC27653366 may position it as a promising candidate for the treatment of different types of cancers.
Insights
Researchers identified ZINC27653366 as a promising compound targeting both Histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90) for cancer therapy. Further validation is needed, but this dual inhibition shows potential for treating various cancers.
Area of Science:
- Oncology
- Computational Chemistry
- Drug Discovery
Background:
- Histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90) are key targets in cancer research due to their roles in protein homeostasis.
- Simultaneous inhibition of HDAC6 and Hsp90 offers synergistic therapeutic potential against cancers.
Purpose of the Study:
- To identify novel compounds capable of inhibiting both HDAC6 and Hsp90 proteins.
- To explore potential synergistic therapeutic strategies for cancer treatment.
Main Methods:
- In-silico screening of 791 molecules from the ZINC15 database against HDAC6 and Hsp90 using molecular docking.
- Selection of top-ranking ligands based on binding scores, followed by ADME prediction and molecular dynamics simulations.
Main Results:
- ZINC27653366 demonstrated the highest inhibitory potential against both HDAC6 and Hsp90 targets.
- Molecular docking, simulations, and ADME studies confirmed ZINC27653366 as a promising dual inhibitor.
Conclusions:
- In silico evaluation suggests ZINC27653366 is a potential candidate for treating various cancers.
- Further in vitro and in vivo studies are necessary to validate the efficacy and safety of ZINC27653366.
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