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Identification of Potential Inhibitors of TGFβR1 for the Treatment of Cancer through Structure-Based Virtual
Saumya Rastogi1, Shashank Shekher Mishra1, Lakhveer Singh2
1School of Pharmaceutical & Population Health Informatics, Faculty of Pharmacy, DIT University, Dehradun, Uttarakhand, 248001.
Abstract:
Globally, cancer is one of the leading causes of death. Resistance to conventional medications, such as chemotherapy and radiation, continues to be a significant challenge in the treatment of cancer despite the availability of numerous medicines. Therefore, the highest priority is to hunt for new therapeutic agents. Transforming growth factor-beta is a pivotal regulatory cytokine that exerts significant influence over cellular processes, particularly emphasizing its role in facilitating and modulating cell proliferation. TGF-β receptor 1, identified as the most promising active site of the TGF-β signaling, is a potent drug target site that has garnered wide attention for developing new anticancer agents. The present investigation investigates the potential natural products as TGFβR1 inhibitors. The SB431542 complexed TGFβR1 protein model was used to screen the natural product database to obtain a compound with high binding potential. NPC247629 has emerged as the best-scored compound among all the screened compounds, demonstrating the highest affinity towards the TGFβR1 regarding docking score -17.54 kcal/mol. The all-atoms MD simulation study indicated that all proposed hits are retained inside the receptor in dynamic states. Additionally, principal component and free energy landscape analysis were performed to explore the binding mechanism of top-hit natural products. The best-screened hits, NPC247629 and NPC60735, have excellent binding affinity and hold a massive potential for TGFβR1 inhibition, paving the way for promising future investigations in cancer treatment.
Insights
Natural compounds NPC247629 and NPC60735 show high potential as transforming growth factor-beta 1 receptor (TGFβR1) inhibitors. These findings offer promising new avenues for developing novel cancer therapeutics to overcome drug resistance.
Area of Science:
- Oncology
- Pharmacology
- Computational Chemistry
Background:
- Cancer remains a leading global cause of death, with drug resistance to conventional therapies posing a significant challenge.
- Transforming growth factor-beta (TGF-β) signaling is crucial in cell proliferation, making its receptor 1 (TGFβR1) a key target for anticancer drug development.
Purpose of the Study:
- To investigate the potential of natural products as inhibitors of TGFβR1.
- To identify novel compounds with high binding affinity to TGFβR1 for cancer treatment.
Main Methods:
- Utilized a molecular docking approach using a SB431542-complexed TGFβR1 protein model to screen a natural product database.
- Conducted all-atom molecular dynamics (MD) simulations, principal component analysis (PCA), and free energy landscape analysis to evaluate binding stability and mechanisms.
Main Results:
- NPC247629 emerged as the top-scoring compound with the highest binding affinity (-17.54 kcal/mol) to TGFβR1.
- MD simulations confirmed the stable binding of screened compounds within the receptor.
- NPC247629 and NPC60735 demonstrated excellent binding affinity and potential for TGFβR1 inhibition.
Conclusions:
- Natural products NPC247629 and NPC60735 exhibit significant potential as TGFβR1 inhibitors.
- These compounds represent promising candidates for further investigation in the development of novel anticancer agents.
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