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Naturally Occurring Plant-Based Anticancerous Candidates as Potential ERK2 Inhibitors: In-Silico Database Mining and
Mahmoud A A Ibrahim1,2, Sara S M Ali1, Alaa H M Abdelrahman1
1Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, 61519, Egypt.
Abstract:
The evolutionarily conserved extracellular signal-regulated kinase 2 (ERK2) is involved in regulating cellular signaling in both normal and pathological conditions. ERK2 expression is critical for human development, while hyperactivation is a major factor in tumor progression. Up to now, there have been no approved inhibitors that target ERK2, and as such, here we report on screening of a naturally occurring plant-based anticancerous compound-activity-target (NPACT) database for prospective ERK2 inhibitors. More than 1,500 phytochemicals were screened using in-silico molecular docking and molecular dynamics (MD) approaches. NPACT compounds with a docking score lower than a co-crystallized LHZ inhibitor (calc. -10.5 kcal/mol) were subjected to MD simulations. Binding energies (ΔGbinding) of inhibitor-ERK2 complexes over the MD course were estimated using an MM-GBSA approach. Based on MM-GBSA//100 ns MD simulations, the steroid zhankuic acid C (NPACT01034) demonstrated greater binding affinity against ERK2 protein than LHZ, with ΔGbinding values of -50.0 and -47.7 kcal/mol, respectively. Structural and energetical analyses throughout the MD course demonstrated stabilization of zhankuic acid C complexed with ERK2 protein. The anticipated ADMET properties of zhankuic acid C indicated minimal toxicity. Moreover, in-silico evaluation of fourteen ERK2 inhibitors in clinical trials demonstrated the higher binding affinity of zhankuic acid C towards ERK2 protein.
Insights
We screened over 1,500 plant compounds for potential extracellular signal-regulated kinase 2 (ERK2) inhibitors. Zhankuic acid C showed superior binding affinity and minimal toxicity, suggesting it as a promising ERK2 inhibitor candidate.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Extracellular signal-regulated kinase 2 (ERK2) is crucial for cellular signaling and human development.
- ERK2 hyperactivation is implicated in tumor progression, yet no approved inhibitors exist.
- Targeting ERK2 presents a therapeutic opportunity for cancer treatment.
Purpose of the Study:
- To identify novel ERK2 inhibitors from a natural product database.
- To evaluate the binding affinity and stability of potential inhibitors using computational methods.
Main Methods:
- Screening of over 1,500 phytochemicals from the NPACT database using in-silico molecular docking.
- Molecular dynamics (MD) simulations and MM-GBSA calculations to assess binding energies.
- In-silico ADMET prediction for toxicity assessment.
Main Results:
- Zhankuic acid C (NPACT01034) exhibited higher binding affinity to ERK2 than the reference inhibitor LHZ (-50.0 vs. -47.7 kcal/mol).
- MD simulations confirmed the stable complex formation between zhankuic acid C and ERK2.
- In-silico ADMET analysis predicted minimal toxicity for zhankuic acid C.
- Zhankuic acid C demonstrated superior binding affinity compared to 14 ERK2 inhibitors in clinical trials.
Conclusions:
- Zhankuic acid C is a potent natural compound with high binding affinity for ERK2.
- Its stable complex formation and favorable predicted ADMET properties make it a promising candidate for further development as an anticancer therapeutic.
- This study highlights the potential of natural products in drug discovery for targeting key signaling pathways.
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