1Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, SAUDI ARABIA
2Department of Basic Medical Science, Faculty of Applied Medical Sciences, Al-Baha University, SAUDI ARABIA
3Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk, SAUDI ARABIA
4Department of Surgery, King Khalid University, Abha, KINGDOM OF SAUDI ARABIA
5Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, SAUDI ARABIA
6Department of Pharmacology, College of Medicine,Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, SAUDI ARABIA
7Almanac Life Science India Private Limited, New Delhi, INDIA
Corresponding author.
Author Notes
Copyright and License information
ABSTRACT
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.