Discovery and Dynamics Behavior of a New Isoform-Selective Histone Deacetylase 2 Inhibitor Targeting the Active-Site Internal Cavity

Abstract

Histone deacetylase 2 (HDAC2), a human epigenetic enzyme, has become one of the most promising targets for anti-HIV-1 latency and viral eradication due to its specific involvement in transcriptional suppression control at the HIV-1 long terminal repeat (LTR) regions. However, chemotherapeutic intervention by specific targeting of HDAC2 activity using inhibitors remains a great challenge. Most HDAC inhibitors have broad activity among HDAC isoforms, resulting in cellular toxicity and undesirable outcomes. Herein, a structure-based drug discovery was implemented to discover new small chemical compounds selective for HDAC2. A total 3,626 compounds retrieved from the Selleck Chemical library were virtually screened against HDAC2 protein structure. As a result, a small-molecule 3-aminopyrazole derivative Danusertib (ZINC06718723) was identified with the lowest binding affinity of -10.9 kcal/mol and a favorable binding pattern. Molecular dynamics (MD) simulations was then performed at 50 ns to investigate the intermolecular interactions within the HDAC2- Danusertib complex, compared to the apo-HDAC, HDAC2-SAHA, and HDAC2-BRD4884 complexes. Detailed energetic estimations from the molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) of the HDAC2- Danusertib complex revealed a strong binding free energy of -41.41 kcal/mol as well as multiple key residues within HDAC2 internal cavity that contribute to the ligand binding. Dynamics behavior of the complex suggests that this candidate ligand conveys its uniquely high affinity by interacting with both the entrance and the internal cavity of the active site and by dampening the fluctuation of the loops surrounding the entry point. These discovered features could also prove useful in guiding future designs of other selective and potent inhibitors against HDAC2.