Thalassemia is a group of anemias that result from inherited defects in the production of the beta chain of hemoglobin. It is stabilized by gamma globin, which combines to form fetal hemoglobin. One therapeutic approach is to target histone deacetylase (HDAC), which plays an important role in controlling beta thalassemia. This study sought to identify a natural inducer for treating this disease.
Methods
Twenty-five Andrographis paniculata compounds were screened using Schrödinger Suite 2020 (Maestro 12.3) for ligand preparation, grid generation, glide extra precision docking and molecular mechanics/generalized born surface area scoring. The HDAC2 crystal structure (Protein Data Bank ID: 4LXZ) was prepared by removing crystallographic water molecules and performing restrained minimization. Top-scoring complexes were subjected to 5-ns molecular dynamics simulations in GROMACS 2019 using the optimized potentials for liquid simulations force field, three interaction site point charge solvation, and standard neutralization and equilibration protocols. Absorption, distribution, metabolism, and excretion properties were predicted using QikProp.
Results
Among the twenty five screened compounds, SRJ09 derivative of andrographolide, ranked among the top candidates based on glide extra precision docking and molecular mechanics/generalized born surface area scores and was therefore selected for further analysis. SRJ09 showed favorable binding to the HDAC2 active site, with interactions comparable to the reference inhibitor 20Y. Absorption, distribution, metabolism, and excretion predictions indicated acceptable drug-likeness, and molecular dynamics simulations demonstrated stable SRJ09–HDAC2 complex behavior over 5 ns.
Conclusions
The plant Andrographis paniculata contains anti-bacterial, anti-inflammatory, and antioxidant qualities that strengthen the immune system. The HDAC inhibitors have also been shown to be potent human fetal hemoglobin inducer to treat beta thalassemia. The finding of SRJ09 derivative of andrographolide, a good docking score with binding affinity for the active site of HDAC2. Glide score and glide energy of 20Y (an HDAC2 inhibitor of target protein) showed similar binding affinity to SRJ09 with bioactive compounds of Andrographis paniculata plant. The results showed that SRJ09 had complied with all ADME requirements. The MDS study produced acceptable RMSD and RMSF results of the bioactive compounds. There was no observable instability between SRJ09 at 5ns molecular dynamic simulation. We concluded that beta thalassemia may manage by the SRJ09 as prospective HDAC2 inhibitor drugs that efficacious. These in-silico findings suggest that SRJ09 may serve as a promising HDAC2 targeting candidate for inducing HbF and potentially managing beta-thalassemia. However, because this study relied solely on computational data, experimental validation through systematic in-vitro and in-vivo studies is essential to confirm its therapeutic relevance.
Full text
https://www.xiahepublishing.com/2572-5505/JERP-2025-00039
The study was recently published in the Journal of Exploratory Research in Pharmacology .
Journal of Exploratory Research in Pharmacology (JERP) publishes original innovative exploratory research articles, state-of-the-art reviews, editorials, short communications that focus on novel findings and the most recent advances in basic and clinical pharmacology, covering topics from drug research, drug development, clinical trials and application.
