Identification of Novel EGFR Inhibitors for the Targeted Therapy of Colorectal Cancer Using Pharmacophore Modelling,
Amrutha Krishnan K1, Sudha George Valavi1, Amitha Joy2
1Department of Applied Science and Humanities, Sahrdaya College of Engineering and Technology, Affiliated to APJ Abdul Kalam Technological University, Kodakara, Thrissur, Kerala, India.
Background:
Colorectal cancer (CRC) is considered the second deadliest cancer in the world. One of the reasons for the occurrence of this cancer is the deregulation of the Epidermal Growth Factor Receptor (EGFR), which plays a critical role in regulating cell division, persistence, differentiation, and migration. The overexpression of the EGFR protein leads to its dysregulation and causes CRC.
Objectives:
Hence, this work aims to identify and validate novel EGFR inhibitors for the treatment of colorectal cancer employing various computer aided techniques such as pharmacophore modeling, docking, molecular dynamic simulation and Quantitative Structure-Activity Relationship (QSAR) analysis.
Methods:
In this work, a shared-featured ligand-based pharmacophore model was generated using the known inhibitors of EGFR. The best model was validated and screened against ZincPharmer and Maybridge databases, and 143 hits were obtained. Pharmacokinetic and toxicological properties of these hits were studied, and the acceptable ligands were docked against EGFR. The best five protein-ligand complexes with binding energy less than -5 kcal/mol were selected. The molecular dynamic simulation studies of these complexes were conducted for 100 nanoseconds (ns), and the results were analyzed. The biological activity of this ligand was calculated using QSAR analysis.
Results:
The best complex with Root Mean Square Deviation (RMSD) 3.429 Å and Radius of Gyration (RoG) 20.181 Å was selected. The Root Mean Square Fluctuations (RMSF) results were also found to be satisfactory. The biological activity of this ligand was found to be 1.38 μM.
Conclusion:
This work hereby proposes the ligand 2-((1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)oxy)-N- (1H-indol-4-yl)acetamide as a potential EGFR inhibitor for the treatment of colorectal cancer. The wet lab analysis must be conducted, however, to confirm this hypothesis.
Insights
Researchers identified a novel Epidermal Growth Factor Receptor (EGFR) inhibitor for colorectal cancer (CRC) treatment using computational methods. This potential drug candidate shows promise for CRC therapy, pending further laboratory validation.
Area of Science:
- Computational chemistry
- Drug discovery
- Oncology
Background:
- Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally.
- Epidermal Growth Factor Receptor (EGFR) deregulation is a key driver in CRC development and progression.
- Targeting EGFR offers a therapeutic strategy for colorectal cancer treatment.
Purpose of the Study:
- To identify and validate novel Epidermal Growth Factor Receptor (EGFR) inhibitors for colorectal cancer (CRC) therapy.
- To employ computational techniques including pharmacophore modeling, docking, and molecular dynamics simulations.
- To perform Quantitative Structure-Activity Relationship (QSAR) analysis for predicting biological activity.
Main Methods:
- Generated a ligand-based pharmacophore model for EGFR inhibitors.
- Screened chemical databases (ZincPharmer, Maybridge) to identify potential hits.
- Performed molecular docking, dynamic simulations, and QSAR analysis on selected candidates.
Main Results:
- Identified 143 potential hits after database screening.
- Selected top five protein-ligand complexes based on binding energy (< -5 kcal/mol).
- Conducted 100 ns molecular dynamic simulations, with the best complex showing satisfactory stability and RMSF.
- Determined a biological activity of 1.38 μM for the lead compound.
Conclusions:
- Proposed a novel compound, 2-((1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)oxy)-N-(1H-indol-4-yl)acetamide, as a potential EGFR inhibitor for colorectal cancer.
- The identified ligand demonstrates promising therapeutic potential for CRC.
- Further experimental validation (wet lab analysis) is recommended to confirm efficacy.
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