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Investigating a Library of Flavonoids as Potential Inhibitors of a Cancer Therapeutic Target MEK2 Using in Silico
Wejdan M AlZahrani1, Shareefa A AlGhamdi1, Sayed S Sohrab2,3
1Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Abstract:
The second leading cause of death in the world is cancer. Mitogen-activated protein kinase (MAPK) and extracellular signal-regulated protein kinase (ERK) 1 and 2 (MEK1/2) stand out among the different anticancer therapeutic targets. Many MEK1/2 inhibitors are approved and widely used as anticancer drugs. The class of natural compounds known as flavonoids is well-known for their therapeutic potential. In this study, we focus on discovering novel inhibitors of MEK2 from flavonoids using virtual screening, molecular docking analyses, pharmacokinetic prediction, and molecular dynamics (MD) simulations. A library of drug-like flavonoids containing 1289 chemical compounds prepared in-house was screened against the MEK2 allosteric site using molecular docking. The ten highest-scoring compounds based on docking binding affinity (highest score: -11.3 kcal/mol) were selected for further analysis. Lipinski's rule of five was used to test their drug-likeness, followed by ADMET predictions to study their pharmacokinetic properties. The stability of the best-docked flavonoid complex with MEK2 was examined for a 150 ns MD simulation. The proposed flavonoids are suggested as potential inhibitors of MEK2 and drug candidates for cancer therapy.
Insights
Researchers identified novel MEK2 inhibitors from flavonoids using computational methods. These compounds show promise as potential drug candidates for cancer therapy, offering new avenues for treatment.
Area of Science:
- Computational drug discovery
- Medicinal chemistry
- Oncology
Background:
- Cancer is a leading global cause of death, necessitating novel therapeutic strategies.
- Mitogen-activated protein kinase kinase (MEK) 1 and 2 (MEK1/2) are validated anticancer targets with approved inhibitors.
- Flavonoids, a class of natural compounds, possess known therapeutic potential.
Purpose of the Study:
- To discover novel MEK2 inhibitors from a flavonoid library using in silico methods.
- To evaluate the drug-likeness and pharmacokinetic properties of potential inhibitors.
- To assess the stability of flavonoid-MEK2 complexes via molecular dynamics simulations.
Main Methods:
- Virtual screening of a 1289-compound flavonoid library against the MEK2 allosteric site using molecular docking.
- Analysis of top-scoring compounds for drug-likeness (Lipinski's Rule of Five) and ADMET properties.
- 150 ns molecular dynamics simulations to evaluate the stability of the best-docked flavonoid-MEK2 complex.
Main Results:
- Molecular docking identified top-scoring flavonoids with high binding affinity (up to -11.3 kcal/mol) to MEK2.
- Selected compounds exhibited favorable drug-like properties and predicted pharmacokinetic profiles.
- Molecular dynamics simulations confirmed the stability of the complex between MEK2 and the lead flavonoid candidate.
Conclusions:
- The study proposes several flavonoids as potential MEK2 inhibitors.
- These identified flavonoids represent promising candidates for further development in cancer therapy.
- Computational approaches are effective for discovering novel anticancer drug leads from natural products.
