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Exploring the potential of Andrographis paniculata for developing novel HDAC inhibitors: an in silico approach
Debalina Das1, Ritesh Banerjee2, Maumita Bandyopadhyay1
1Plant Molecular Cytogenetics and Plant Biotechnology Laboratory, Department of Botany, Centre of Advanced Studies, University of Calcutta, Kolkata, West Bengal, India.
Abstract:
Cancer is one of the dreaded diseases of the twentieth century, emerging the major global causes of human morbidity. Cancer research in the last 15 years has provided unprecedented information on the role of epigenetics in cancer initiation and progression. Histone deacetylases (HDACs) are recognized as important epigenetic markers in cancer, whose overexpression leads to increased metastasis and angiogenesis. In the current study, thirty-four (34) compounds from Andrographis paniculata were screened for the identification of potential candidate drugs, targeting three Class I HDACs (Histone deacetylases), namely HDAC1 (PDB id 5ICN), HDAC3 (PDB id 4A69) and HDAC8 (PDB id 5FCW) through computer-assisted drug discovery study. Results showed that some of the phytochemicals chosen for this study exhibited significant drug-like properties. In silico molecular docking study further revealed that out of 34 compounds, the flavonoid Andrographidine E had the highest binding affinities towards HDAC1 (-9.261 Kcal mol-1) and 3 (-9.554 Kcal mol-1) when compared with the control drug Givinostat (-8.789 and -9.448 Kcal mol-1). The diterpenoid Andrographiside displayed the highest binding affinity (-9.588 Kcal mol-1) to HDAC8 compared to Givinostat (-8.947 Kcal mol-1). Statistical analysis using Principal Component Analysis tool revealed that all 34 phytocompounds could be clustered in four statistical groups. Most of them showed high or comparable inhibitory potentials towards HDAC target protein. Finally, the stability of top-ranked complexes (Andrographidine E-HDAC1 and HDAC3; Andrographiside-HDAC8) at the physiological condition was validated by Molecular Dynamic Simulation and MM-PBSA study.Communicated by Ramaswamy H. Sarma.
Insights
This study screened 34 compounds from Andrographis paniculata for potential anti-cancer activity by targeting Histone deacetylases (HDACs). Andrographidine E and Andrographiside showed high binding affinities, suggesting their potential as novel drug candidates for cancer therapy.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Cancer is a leading global cause of morbidity, with epigenetics playing a crucial role in its initiation and progression.
- Histone deacetylases (HDACs) are epigenetic regulators often overexpressed in cancer, promoting metastasis and angiogenesis.
- Targeting HDACs presents a promising therapeutic strategy for cancer treatment.
Purpose of the Study:
- To identify potential anti-cancer drug candidates from *Andrographis paniculata* targeting Class I HDACs (HDAC1, HDAC3, HDAC8).
- To evaluate the drug-like properties and binding affinities of selected phytochemicals against HDAC targets using computational methods.
Main Methods:
- *In silico* screening of 34 compounds from *Andrographis paniculata* against HDAC1 (PDB: 5ICN), HDAC3 (PDB: 4A69), and HDAC8 (PDB: 5FCW).
- Molecular docking studies to assess binding affinities, comparing with the control drug Givinostat.
- Principal Component Analysis (PCA) for statistical grouping of phytocompounds.
- Molecular Dynamic (MD) Simulation and MM-PBSA for validating the stability of top-ranked complexes.
Main Results:
- Several phytochemicals exhibited significant drug-like properties.
- Flavonoid Andrographidine E showed highest binding affinities to HDAC1 (-9.261 Kcal/mol) and HDAC3 (-9.554 Kcal/mol).
- Diterpenoid Andrographiside displayed the highest binding affinity to HDAC8 (-9.588 Kcal/mol).
- PCA clustered the 34 compounds into four groups, indicating varied inhibitory potentials.
- MD simulations and MM-PBSA confirmed the stability of Andrographidine E-HDAC1/HDAC3 and Andrographiside-HDAC8 complexes.
Conclusions:
- *Andrographis paniculata* compounds, particularly Andrographidine E and Andrographiside, demonstrate significant potential as inhibitors of Class I HDACs.
- These findings support the development of novel anti-cancer therapeutics derived from natural products targeting epigenetic mechanisms.
