Blocking Protein kinase C signaling pathway: mechanistic insights into the anti-leishmanial activity of prospective herbal drugs from Withania somnifera
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BACKGROUND: Leishmaniasis is caused by several species of leishmania protozoan and is one of the major vector-born diseases after malaria and sleeping sickness. Toxicity of available drugs and drug resistance development by protozoa in recent years has made Leishmaniasis cure difficult and challenging. This urges the need to discover new antileishmanial-drug targets and antileishmanial-drug development. RESULTS: Tertiary structure of leishmanial protein kinase C was predicted and found stable with a RMSD of 5.8Å during MD simulations. Natural compound withaferin A inhibited the predicted protein at its active site with -28.47 kcal/mol binding free energy. Withanone was also found to inhibit LPKC with good binding affinity of -22.57 kcal/mol. Both withaferin A and withanone were found stable within the binding pocket of predicted protein when MD simulations of ligand-bound protein complexes were carried out to examine the consistency of interactions between the two. CONCLUSIONS: Leishmanial protein kinase C (LPKC) has been identified as a potential target to develop drugs against Leishmaniasis. We modelled and refined the tertiary structure of LPKC using computational methods such as homology modelling and molecular dynamics simulations. This structure of LPKC was used to reveal mode of inhibition of two previous experimentally reported natural compounds from Withania somnifera - withaferin A and withanone.
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A 28kDA nontoxic, acidic protease inhibitor glycoprotein extracted from Withania somnifera tubers imparts fungistatic effect to Fusarium oxysporum, Aspergillus flavus, and Fusarium verticillioides by inhibiting hyphal growth and spore germination.
“A 28kDA nontoxic, acidic protease inhibitor glycoprotein extracted from WS tubers imparted a fungistatic effect to many phytopathogenic fungi like Fusarium oxysporum, Aspergillus flavus, and Fusarium verticillioides by inhibiting hyphal growth and spore germination [115].”
From Withania somnifera (L.) Dunal (Ashwagandha): A comprehensive review on ethnopharmacology, pharmacotherapeutics, biomedicinal and toxicological aspects (2021) · cites this paper as [115]
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Soumya, N., Tandan, H., Damre, M. V., Gangwal, R. P., Sangamwar, A. T., & Singh, S. (2016) · Gene · doi:10.1016/j.gene.2016.01.011 · Cited by 3 · see citing works
Bora, K., Kumar, S., Kanaujia, S. P., & Dubey, V. K. (2025) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2025.106883 · Cited by 2 · see citing works
Gouri, V., Kanojia, A., Kumar, A., & Kumar, A. (2026) · Journal of Molecular Modeling · doi:10.1007/s00894-026-06647-1 · Cited by 2 · see citing works
Çolak, N. G. (2025) · Studies in natural products chemistry · doi:10.1016/b978-0-443-23752-2.00011-6 · Cited by 1 · see citing works
Park, J. W., Lee, G., Kim, J., & Choi, H. (2021) · Plant Breeding and Biotechnology · doi:10.9787/pbb.2021.9.3.213 · Cited by 1 · see citing works
Molecular docking study of bioactive phytochemicals against infectious diseases
Sahu, S. K., Mahender, T., Singh, I., Wadhwa, P. K., Kaur, P., & Bansal, K. K. (2023) · Elsevier eBooks · doi:10.1016/b978-0-443-19143-5.00011-6
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Targeting Leishmania kinases: The therapeutic potential of natural products
Sharma, P., & Somlata (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-27544-9.00002-7
- Authors
- Grover, A., Katiyar, S. P., Jeyakanthan, J., Dubey, V. K., & Sundar, D.
- Affiliations
- Indian Institute of Technology Delhi (IN)
- Alagappa University (IN)
- Indian Institute of Technology Guwahati (IN)
- Corresponding author
- Sundar, Durai
- Venue
- BMC Genomics
- Published
- 2012-12
- Volume
- 13
- Issue
- S7
- Pages
- S20-S20
- ISSN
- 1471-2164 (ISSN-L)
- PMC
- PMC3521472
- OpenAlex
- W1865104699
- Cited by
- 52
- References
- 49
- Citations by year
- 2026: 3 · 2025: 3 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 7 · 2019: 1 · 2018: 6 · 2017: 9 · 2016: 3 · 2015: 6 · 2014: 1 · 2012: 1
- FWCI
- 2.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- BMC Genomics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Department of Biotechnology, Ministry of Science and Technology, India
- Indian Institute of Technology Delhi
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Research on Leishmaniasis Studies
- Health Sciences › Medicine › Complementary and alternative medicine › Phytochemicals and Medicinal Plants
- Keywords
- leishmaniasis, Withania somnifera, withaferin A, withanone, antileishmanial activity, protein kinase C inhibition, herbal drugs, drug target identification, protein tertiary structure prediction, homology modeling, molecular dynamics simulation, binding free energy
- MeSH terms
- Antiprotozoal Agents, Binding Sites, Leishmania, Protein Kinase C, Thermodynamics, Triterpenes, Signal Transduction, Protozoan Proteins, Catalytic Domain, Herbal Medicine, Withania, Withanolides, Molecular Docking Simulation
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