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Sanggenol B, a plant bioactive, as a safer alternative to tackle cancer by antagonising human FGFR
Achyuta Nagaraj1, Sriram Srinivasa Raghavan1,2, Ayyadurai Niraikulam3
1Department of Crystallography and Biophysics, University of Madras, Chennai, India.
Abstract:
Fibroblast Growth Receptor Factor (FGFR) are a family of proteins which are, in addition to their biological role, are involved in various pathological functions, such as cancer cellular proliferation, and metastasis. Deregulation of FGFRs at various points could result in malignancy. A conformational transition of the DFG (Asp-Phe-Gly) motif can switch the enzyme from a catalytically active (DFG-in) to an inactive (DFG-out) state. There are a few FDFR inhibitors which have received approval from the FDA, but these have adverse side effects. Hence, there is a demand for safer alternatives. With this aim, Ligand and Structure based virtual screening was carried to identify suitable lead molecule. In this process, Four Featured atom-based 3D Pharmacophore with quantitative structure-activity relationship analysis (3D-QSAR) was developed. The External validation of the hypothesis was carried invoking criteria such as Area under the ROC curve. Natural plant compound databases such as the Traditional Chinese medicine, NPACT and the ZINC Natural databases were chosen for pharmacophore filtering, which was followed by virtual screening against FGFR isoforms. The compound Sanggenol B was identified as the most suitable lead molecule. Structural stability of the protein-ligand complex and interactions of the ligand (Sanggenol B & the reference compound Ponatinib) with FGFR were analysed for 1000 ns (triplicate) by means of molecular simulation and the binding free energy was calculated using MMGBSA. Sanggenol B (PubChem CID: 15233694) binds effectively at the active site with favourable energies and is proposed as a safe alternative from a natural source.Communicated by Ramaswamy H. Sarma.
Insights
Researchers identified Sanggenol B, a natural compound, as a promising FGFR inhibitor. This discovery offers a potentially safer alternative to existing cancer drugs with fewer adverse effects.
Area of Science:
- Medicinal Chemistry
- Computational Biology
- Pharmacology
Background:
- Fibroblast Growth Factor Receptors (FGFRs) are implicated in cancer proliferation and metastasis.
- FGFR deregulation can lead to malignancy, necessitating targeted therapies.
- Existing FGFR inhibitors have significant adverse effects, driving the search for safer alternatives.
Purpose of the Study:
- To identify novel, safer lead molecules targeting FGFRs using computational approaches.
- To develop and validate a pharmacophore model for FGFR inhibition.
- To evaluate natural compounds as potential therapeutic agents against FGFR-driven cancers.
Main Methods:
- Ligand and structure-based virtual screening of natural product databases.
- Development and external validation of a four-featured atom-based 3D Pharmacophore model with 3D-QSAR.
- Molecular dynamics simulations and MMGBSA calculations to assess protein-ligand complex stability and binding free energy.
Main Results:
- Sanggenol B was identified as the most promising lead compound through virtual screening.
- Molecular simulations confirmed stable binding of Sanggenol B to the FGFR active site.
- Sanggenol B demonstrated favorable binding free energy, comparable to the reference inhibitor Ponatinib.
Conclusions:
- Sanggenol B, a natural compound, effectively binds to FGFRs with favorable energetics.
- This study proposes Sanggenol B as a potential safe and effective therapeutic alternative for FGFR-related malignancies.
- Natural product-derived compounds represent a valuable resource for developing novel anti-cancer agents.
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