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Indian Journal of Pharmaceutical Education and ResearchNOW IN
Article

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

Ayyub Ali Patel1, Hani Alothaid2, Ayaz Khurram Mallick1, Adel Ibrahim Alalawy3, Rasha Tarek Mirdad4, Mahmoud Tarek Mirdad5, Mohammed Tarek Mirdad5, Marya Ahsan6, Mohammed Tarique7★★ Corresponding author

  1. 1Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, SAUDI ARABIA.
  2. 2Department of Basic Medical Science, Faculty of Applied Medical Sciences, Al-Baha University, SAUDI ARABIA.
  3. 3Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, SAUDI ARABIA.
  4. 4Department of Surgery, King Khalid University, Abha, KINGDOM OF SAUDI ARABIA.
  5. 5Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, SAUDI ARABIA.
  6. 6Department of Pharmacology, College of Medicine,Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, SAUDI ARABIA.
  7. 7Almanac Life Science India Private Limited, New Delhi, INDIA.

CORRESPONDENCE

Mohammed Tarique

Almanac Life Science India Private Limited, New Delhi, INDIA.

tariqueaiims@gmail.com

Received: 28-12-2023; Revised: 21-02-2024; Accepted: 02-05-2024.

Volume 58, Issue 3 · pp. 802–813 · PUBLISHED Jul-Sep 2024 · DOI: 10.5530/ijper.58.3.88

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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.

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    Patel, A. A., Alothaid, H., Mallick, A. K., Alalawy, A. I., Mirdad, R. T., Mirdad, M. T., Mirdad, M. T., Ahsan, M., & Tarique, M. (2024). Inhibiting Cancer Progression through Targeting HDAC2 with Novel Ligands: A Dynamic Insights through Virtual Screening and Simulation. Indian Journal of Pharmaceutical Education and Research, 58(3), 802–813. https://doi.org/10.5530/ijper.58.3.88