Inhibiting Cancer Progression through Targeting HDAC2 with Novel Ligands: A Dynamic Insights through Virtual Screening and Simulation

Background Cancer is a multifaceted disease characterized by uncontrolled cell growth and represents a significant global health challenge. The intricate origins of cancer involve various factors that may act independently or collectively, contributing to its initiation and progression and resulting in the dynamic nature of the disease. Aim The current focus of research is to elucidate the role of histone acetylation in cancer progression. Materials and Methods A key area of interest is histone deacetylation, which intensifies ion-based interactions between negatively charged DNA and positively charged histones. Histone deacetylation, specifically the removal of acetyl groups from histone proteins by Histone Deacetylase 2 (HDAC2), plays a pivotal role in regulating gene expression. The primary objective of this study was to identify molecular inhibitors targeting HDAC2 through Structure-Based Virtual Screening (SBVS) using an extensive MCULE chemical compound database. After the application of stringent filters, 100 promising compounds were selected for further investigation. Results Docking simulations using DockThor revealed 16 molecules with superior free binding energies compared to the control (entinostat). Subsequently, ten compounds meeting the Absorption, Distribution, Metabolism and Excretion (ADME) rules were chosen based on the Egan-Egg permeation predictive model. The top two ligands, along with the positive control entinostat, underwent a five-nanosecond molecular dynamics simulation. The evaluation criteria included toxicity profiling, physiochemical properties, lipophilicity, solubility, pharmacokinetics, druglikeness, medicinal chemistry attributes, Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF) and Radius of Gyration (Rg). Conclusion Through these analyses, ligand MCULE-5097730104-0-3 emerged as a promising HDAC2 inhibitor, exhibiting potential efficacy in combating cancer progression.