Applying comparative molecular modelling techniques on diverse hydroxamate-based HDAC2 inhibitors: an attempt to identify promising structural features for potent HDAC2 inhibition

ABSTRACT

Histone deacetylase 2 (HDAC2) has been implicated in a variety of cardiovascular and neurodegenerative disorders as well as in cancers. Thus, HDAC2 has become an exclusive target for anticancer drug development. Therefore, the development of newer HDAC2 inhibitors in disease conditions is a prime goal to restrain such a scenario. Although a handful of HDAC inhibitors was accepted for the treatment of HDAC-related disease conditions, the non-selective nature of these entities is one of the major setbacks in the treatment of specific HDAC isoform-related pathophysiology. In this framework, the analyses of pre-existing molecules are essential to identify the important structural features that can fulfil the requirements for the cap and linker moieties to obtain potent and effective HDAC2 inhibition. Thus, in this study, the implementation of a combined comparative 2D and 3D molecular modelling techniques was done on a group of 92 diverse hydroxamate derivatives having a wide range of HDAC2 inhibitory potency. Besides other crucial features, this study upheld the importance of groups like triazole and benzyl moieties along with the molecular fields that are crucial for regulating HDAC2 inhibition. The outcomes of this study may be employed for the designing of HDAC2 inhibitors in future.

KEYWORDS:

• HDAC2
• MLR
• LDA
• recursive partitioning
• CoMFA
• CoMSIA

Acknowledgements

VY is grateful to the All India Council for Technical Education (AICTE), New Delhi for awarding a scholarship. SB is thankful to the Swami Vivekananda Merit-cum-Means (SVMCM) scholarship, Govt. of West Bengal, India for awarding the fellowship. SKB sincerely thanks the Indian Council of Medical Research (ICMR), New Delhi, India for awarding the senior research fellowship (SRF) [FILE NO.: 45/29/2019-PHA, dated: 21-06-2019]. The authors are thankful to Dr. Balaram Ghosh of the Department of Pharmacy, BITS-Pilani, Hyderabad campus, India for his careful reading and valuable suggestions to improve the quality of the manuscript. TJ is thankful for the financial support from RUSA 2.0 of UGC, New Delhi, India to Jadavpur University, Kolkata, India. We are very much thankful to the Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India for providing the research facilities.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2021.2013317

Additional information

Funding

This work was supported by the Indian Council of Medical Research (ICMR), Govt. of India.