First report on analysis of chemical space, scaffold diversity, critical structural features of HDAC11 inhibitors.

In the histone deacetylase (HDAC) family, HDAC11 is the smallest and a single member under the class IV subtype. It is important as a drug target mainly in cancer, inflammatory and autoimmune diseases. The design and development of selective HDAC11 inhibitors is quite a challenge for the chemist community due to the unavailability of the crystal structure of HDAC11. Ligand-based drug design (LBDD) strategies are the hope to speed up the development of its inhibitors. Here, an in-depth analysis of 712 HDAC11 inhibitors is performed through compound space networks and various cheminformatics approaches. The analyses demonstrated significant clustering of similar compounds based on their chemical structures, offering valuable insights into the chemical space occupied by HDAC11 inhibitors. Furthermore, the current work aimed to develop robust classification-based QSAR models that deliver the essential structural fingerprints. This study highlighted that the compounds bearing scaffolds such as isoindoline, benzimidazole, carboxamide/hydroxamate moieties, etc., are important for HDAC11 inhibitors. Molecular docking and MD simulations further provide an in-depth analysis of the binding interaction of the identified fingerprints in the catalytic site of HDAC11. In brief, our study delivers some important structural attributes that will aid medicinal chemists in designing and developing future potent HDAC11 inhibitors.