A comparative quantitative structural assessment of benzothiazine-derived HDAC8 inhibitors by predictive ligand-based drug designing approaches

ABSTRACT

Histone deacetylase 8 (HDAC8) is a verified biomolecular target associated with diverse diseases including cancer. Though several HDAC inhibitors emerged effective against such diseases, no selective HDAC8 inhibitor is approved to date. Therefore, the development of potent HDAC8-selective inhibitors is inevitable to combat such diseases. Here, some benzothiazine-derived HDAC8 inhibitors were considered for a comparative QSAR analysis which may elucidate the prime structural components responsible for modulating their efficacy. Several outcomes from these diverse modelling techniques justified one another and thus validated each other. The ligand-based pharmacophore modelling study identified ring aromatic, positive ionizable, and hydrophobic features as essential structural attributes for HDAC8 inhibition. Besides, MLR, HQSAR and field-based 3D-QSAR studies signified the utility of the positive ionizable and hydrophobic features for potent HDAC8 inhibition. Again, the field-based 3D-QSAR study provided useful insight regarding the substitution in the fused phenyl ring. Moreover, the current observations also validated the previously reported molecular docking observations. Based on the outcomes, some new molecules were designed and predicted. Therefore, this comparative structural analysis of these HDAC8 inhibitors will surely assist in the development of potent HDAC8 inhibitors as promising anticancer therapeutics in the future.

KEYWORDS:

• Histone deacetylase 8
• benzothiazine derivatives
• pharmacophore mapping
• CoMFA
• CoMSIA
• binding mode of analysis

Acknowledgements

SB is thankful to the Swami Vivekananda Merit-cum-Means (SVMCM) scholarship, Govt. of West Bengal, India for awarding the fellowship. NA is thankful to the authority of Jadavpur University for providing the research grant to conduct the research work. The authors are thankful to the Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India for providing the research facilities. The authors also thank Dr. Balaram Ghosh, BITS-Pilani, Hyderabad Campus, India for his fruitful suggestion during the preparation of this manuscript. The authors also thank Mr. Vishal Saha of Department of Pharmaceutical Technology, Jadavpur University for his technical assistance.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2022.2155241

Additional information

Funding

This work was supported by the research grant provided by Jadavpur University; Swami Vivekananda Merit-cum-Means (SVMCM) scholarship, Govt. of West Bengal, India.