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

Abstract

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.