Screening of Phytocompounds for Identification of Prospective Histone Deacetylase 1 (HDAC1) Inhibitor: An In Silico Molecular Docking, Molecular Dynamics Simulation, and MM-GBSA Approach.

The upregulation of HDAC1 facilitate the induction of epigenetic repression of genes responsible for suppressing tumourigenesis, thereby triggering the development of cancer. HDAC1 inhibitors have thus emerged as possible therapeutic approaches against a variety of human malignancies, as they can inhibit the activity of certain HDACs, repair the overexpression of tumour suppressor genes, and induce cell differentiation, cell cycle arrest, and apoptosis. In this study, among 810 virtually screened compounds, Pinocembrin (PHUB000396) had a significant binding affinity (-7.99 kcal/mol). In molecular dynamics simulation (MD) studies for 200 ns time scale, the compound Pinocembrin effectively undergoes conformational optimization, thereby enabling its accommodation within the active site of the receptor. This outcome serves as a rational for the observed binding affinity. The optimal binding free energy calculations using the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) (-35.86 ± 7.52 kcal/mol) showed the significant role of van der Waals forces and Coulomb interactions in the stability of the respective complex. The pharmacokinetic study showed its potential as a lead compound. The in-silico cytotoxicity prediction also confirmed its potential as an active anticancer phytocompound in lung and brain cancer. Therefore, it can be predicted that Pinocembrin could be a useful bioactive compound as an HDAC1 inhibitor and could be used in developing epigenetic therapy in cancer such as brain cancer and lung cancer to regulate gene expression.