Essential elements regulating HDAC8 inhibition: a classification based structural analysis and enzyme-inhibitor interaction study of hydroxamate based HDAC8 inhibitors

Abstract

Histone deacetylase 8 (HDAC8) expressions are correlated with a variety of cancer and tumor conditions. For the pathophysiological contributions of HDAC8, it is classified as an important target for cancer research. The hydroxamate derivatives are identified as more efficient HDAC8 inhibitors. However, strong chelating properties of hydroxamate group with the catalytic zinc ion of HDAC8 resulted in some demerits. Hence, in this current study, classification based chemoinformatic approaches including Bayesian modeling and recursive partitioning studies were conducted on a large and diverse set of 607 hydroxamates having less, very poor to high HDAC8 inhibitory properties. The main motto of this study is to identify and analyze the pivotal structural features of the cap and linker moieties required to obtain better HDAC8 inhibition. Moreover, a scrutiny of the HDAC8 crystal structure bound inhibitors was performed to correlate enzyme-inhibitor interactions with important molecular features resulted from these two classification-based models. The approach may be used to design novel HDAC8 inhibitors.

Communicated by Ramaswamy Sarma

Keywords:

• Hydroxamate derivative
• HDAC8 inhibitor
• QSAR
• Bayesian classification
• recursive partitioning
• enzyme-inhibitor interaction

Disclosure statement

The authors have no conflict of interests.

Additional information

Funding

Suvankar Banerjee is grateful to the RUSA 2.0 of University Grant Commission (UGC), New Delhi, India to Jadavpur University, Kolkata, India for awarding fellowship [REF. NO: R-11/1030/19, Dated: 30-07-2019] for awarding a fellowship. Sk. Abdul Amin sincerely acknowledges Council of Scientific and Industrial Research (CSIR), New Delhi, India for awarding the Senior Research Fellowship (SRF) [FILE NO.: 09/096(0967)/2019-EMR-I, Dated: 01-04-2019]. Nilanjan Adhikari is grateful to CSIR, New Delhi, India for providing research associateship (RA) [FILE NO.: 09/096(0966)/2019-EMR-I, Dated: 28-03-2019]. Tarun Jha is also thankful for the financial support from RUSA 2.0 of UGC, New Delhi, India to Jadavpur University, Kolkata, India. We also thank the support from the Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India for providing the research facilities.