Discovery of the allosteric inhibitor from actinomyces metabolites to target EGFRCSTMLR mutant protein: molecular modeling and free energy approach

by Selleckchem | Sep 20 2023

EGFR (epidermal growth factor receptor), a surface protein on the cell, belongs to the tyrosine kinase family, responsible for cell growth and proliferation. Overexpression or mutation in the EGFR gene leads to various types of cancer, i.e., non-small cell lung cancer, breast, and pancreatic cancer. Bioactive molecules identified in this genre were also an essential source of encouragement for researchers who accomplished the design and synthesis of novel compounds with anticancer properties. World Health Organization (WHO) report states that antibiotic resistance is one of the most severe risks to global well-being, food safety, and development. The world needs to take steps to lessen this danger, such as developing new antibiotics and regulating their use. In this study, 6524 compounds derived from Streptomyces sp. were subjected to drug-likeness filters, molecular docking, and molecular dynamic simulation for 1000 ns to find new triple mutant EGFRCSTMLR (EGFR-L858R/T790M/C797S) inhibitors. Docking outcomes revealed that five compounds showed better binding affinity (- 9.074 to - 9.3 kcal/mol) than both reference drug CH7233163 (- 6.11 kcal/mol) and co-crystallized ligand Osimertinib (- 8.07 kcal/mol). Further, molecular dynamic simulation confirmed that ligand C_42 exhibited the best interaction at the active site of EGFR protein and comprised a better average radius of gyration (3.87 Å) and average SASA (Solvent Accessible Surface Area) (82.91 Å2) value than co-crystallized ligand (4.49 Å, 222.38 Å2). Additionally, its average RMSD (Root Mean Square Deviation) (3.25 Å) and RMSF (Root Mean Square Fluctuation) (1.54 Å) values were highly similar to co-crystallized ligand (3.07 Å, 1.54 Å). Compared to the reference ligand, it also demonstrated conserved H-bond interactions with the residues MET_793 and GLN_791 with strong interaction probability. In conclusion, we have found a potential drug with no violation of the rule of three, Lipinski's rule of five, and 26 other vital parameters having great potential in medicinal and pharmaceutical industries applications and can overcome synthetic drug issues.

Comments:

The study you described focused on the design and synthesis of novel compounds with anticancer properties targeting the triple mutant form of the epidermal growth factor receptor (EGFR), known as EGFRCSTMLR (EGFR-L858R/T790M/C797S). Overexpression or mutation in the EGFR gene is associated with various types of cancer, such as non-small cell lung cancer, breast cancer, and pancreatic cancer.

The researchers employed a multi-step approach to identify potential inhibitors for EGFRCSTMLR. They started with a set of 6524 compounds derived from Streptomyces sp. These compounds were then subjected to drug-likeness filters, molecular docking, and molecular dynamic simulation.

The docking results indicated that five compounds exhibited better binding affinity to EGFRCSTMLR compared to both the reference drug CH7233163 and the co-crystallized ligand Osimertinib. The binding affinity of the compounds ranged from -9.074 to -9.3 kcal/mol.

To further assess the stability and behavior of the compounds, molecular dynamic simulations were performed for 1000 ns. One particular compound, referred to as C_42, showed the best interaction at the active site of the EGFR protein. It also demonstrated favorable average values for the radius of gyration (3.87 Å) and solvent accessible surface area (82.91 Å2), compared to the co-crystallized ligand. The compound exhibited similar average values of root mean square deviation (RMSD) and root mean square fluctuation (RMSF) to the co-crystallized ligand, indicating its structural stability.

Moreover, C_42 maintained conserved hydrogen bond interactions with the residues MET_793 and GLN_791, with a high interaction probability. This further supported its potential as a drug candidate.

The study concluded that compound C_42 has promising potential in medicinal and pharmaceutical applications, as it adheres to important parameters such as the rule of three, Lipinski's rule of five, and 26 other vital parameters. The researchers suggested that this compound could address challenges associated with synthetic drugs and may have significant implications for the development of new therapeutic options.

It is important to note that the information provided here is based on the description you provided, and I don't have access to the specific details or results of the actual study.