Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jan 11:14:1231671.
doi: 10.3389/fphar.2023.1231671. eCollection 2023.

Computational insights into the stereo-selectivity of catechins for the inhibition of the cancer therapeutic target EGFR kinase

Mohd Rehan  1   2 , Firoz Ahmed  3   4 , Mohammad Imran Khan  5 , Hifzur Rahman Ansari  6 , Shazi Shakil  1   2   7 , Moustafa E El-Araby  8 , Salman Hosawi  9 , Mohammad Saleem  10   11
Affiliations

Computational insights into the stereo-selectivity of catechins for the inhibition of the cancer therapeutic target EGFR kinase

Mohd Rehan et al. Front Pharmacol. .

Abstract

The epidermal growth factor receptor (EGFR) plays a crucial role in regulating cellular growth and survival, and its dysregulation is implicated in various cancers, making it a prime target for cancer therapy. Natural compounds known as catechins have garnered attention as promising anticancer agents. These compounds exert their anticancer effects through diverse mechanisms, primarily by inhibiting receptor tyrosine kinases (RTKs), a protein family that includes the notable member EGFR. Catechins, characterized by two chiral centers and stereoisomerism, demonstrate variations in chemical and physical properties due to differences in the spatial orientation of atoms. Although previous studies have explored the membrane fluidity effects and transport across cellular membranes, the stereo-selectivity of catechins concerning EGFR kinase inhibition remains unexplored. In this study, we investigated the stereo-selectivity of catechins in inhibiting EGFR kinase, both in its wild-type and in the prevalent L858R mutant. Computational analyses indicated that all stereoisomers, including the extensively studied catechin (-)-EGCG, effectively bound within the ATP-binding site, potentially inhibiting EGFR kinase activity. Notably, gallated catechins emerged as superior EGFR inhibitors to their non-gallated counterparts, revealing intriguing binding trends. The top four stereoisomers exhibiting high dock scores and binding energies with wild-type EGFR comprise (-)-CG (-)-GCG (+)-CG, and (-)-EGCG. To assess dynamic behavior and stability, molecular dynamics simulations over 100 ns were conducted for the top-ranked catechin (-)-CG and the widely investigated catechin (-)-EGCG with EGFR kinase. This study enhances our understanding of how the stereoisomeric nature of a drug influences inhibitory potential, providing insights that could guide the selection of specific stereoisomers for improved efficacy inexisting drugs.

Keywords: EGCG; diastereomers; drug delivery; gallocatechin; gallocatechin gallate; kinases; small molecules; spatial isomers.

PubMed Disclaimer

Conflict of interest statement

Author MS was employed by LabCorp Drug Development Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
(A–D) Four stereoisomers of catechin. Two chiral centers are shown on carbon 2 and carbon 3. The stereoisomers vary in the positioning of chemical groups at carbon 2 and carbon 3. The solid bond indicates that it is protruding toward us, whereas the dashed bond indicates that it is going away from us. The “R” (Latin: “rectus”, means right) and “S” (Latin: “sinister”, means left) notations for the “2” and “3” positions of the chiral carbons are shown for each stereoisomer. Based on these two bonds at carbon 2 and carbon 3, there are two trans isomers called catechin, shown in panel (A) and panel (B), and two cis isomers called epicatechin, shown in panel (C) and panel (D).
FIGURE 2
FIGURE 2
(A–D) The two-dimensional structures of the four major natural catechins. The chiral centers are shown as carbon 2 and carbon 3. Based on the orientation of the bonds joining other chemical groups to these chiral carbons, every catechin derivative has two trans isomers and two cis (epi) isomers, making a total of four stereoisomers.
FIGURE 3
FIGURE 3
(A, B) Self-docking analyses of the bound reference ligands, compound 41a for wild-type EGFR (A) and PD168393 for mutant EGFR (B). The ligand binding sites of the proteins are depicted as surfaces in light orange, with the docked pose of the bound reference ligand with backbone in pink and the original bound pose in green.
FIGURE 4
FIGURE 4
(A–I) Protein-ligand interaction plots of the bound reference ligand (compound 41a) and the top eight ranked stereoisomers of catechin derivatives with wild-type EGFR. The amino acid residues forming hydrophobic interactions are shown as comb-like structures with bristles. The interacting residues in common with those of the bound reference ligand are encircled. The ligand and the residues forming hydrogen bonding interactions are shown as ball-and-stick representations. The color of the balls distinguishes various atom types: the black balls represent carbon atoms, the red balls represent oxygen atoms, the blue balls represent nitrogen atoms, the yellow balls represent sulfur atoms, and the green balls represent fluorine atoms. The hydrogen bonds are shown as green dashed lines labeled with bond lengths (in Å).
FIGURE 5
FIGURE 5
(A–I) Protein-ligand interaction plots of the bound reference ligand (compound 41a) and the bottom eight ranked stereoisomers of catechin derivatives with wild-type EGFR. The amino acid residues forming hydrophobic interactions are shown as comb-like structures with bristles. The interacting residues in common with those of the bound reference ligand are encircled. The ligand and the residues forming hydrogen bonding interactions are shown as ball-and-stick representations. The color of the balls distinguishes various atom types: the black balls represent carbon atoms, the red balls represent oxygen atoms, the blue balls represent nitrogen atoms, the yellow balls represent sulfur atoms, and the green balls represent fluorine atoms. The hydrogen bonds are shown as green dashed lines labeled with bond lengths (in Å).
FIGURE 6
FIGURE 6
The stereoisomers of catechin derivatives with their binding energy scores for wild-type (purple) and mutant L858R (green) EGFR. The binding energies of stereoisomers for the wild-type shown as purple bars are arranged in decreasing absolute values of binding energies. The gallated catechin derivatives clustered together and stood out with the non-gallated ones in having higher scores for the binding energies for both the wild-type and the mutant EGFR.
FIGURE 7
FIGURE 7
(A–I) Protein-ligand interaction plots of the bound reference ligand (PD168393) and the stereoisomers of catechin derivatives with mutant L858R EGFR. The order of stereoisomers appearing in this figure is the same as in Figure 4. The amino acid residues forming hydrophobic interactions are shown as comb-like structure with bristles. The interacting residues in common with those of the bound reference ligand are encircled. The ligand and the residues forming hydrogen bonding interactions are shown as ball-and-stick representations. The color of the balls distinguishes various atom types: the black balls represent carbon atoms, the red balls represent oxygen atoms, the blue balls represent nitrogen atoms, the yellow balls represent sulfur atoms, and the green balls represent bromine atoms. The hydrogen bonds are shown as green dashed lines labeled with bond lengths (in Å).
FIGURE 8
FIGURE 8
(A–I) Protein-ligand interaction plots of the bound reference ligand (PD168393) and the stereoisomers of catechin derivatives with mutant L858R EGFR. The order of stereoisomers appearing in this figure is the same as in Figure 5. The amino acid residues forming hydrophobic interactions are shown as comb-like structure with bristles. The interacting residues in common with those of the bound reference ligand are encircled. The ligand and the residues forming hydrogen bonding interactions are shown as ball-and-stick representations. The color of the balls distinguishes various atom types: the black balls represent carbon atoms, the red balls represent oxygen atoms, the blue balls represent nitrogen atoms, the yellow balls represent sulfur atoms, and the green balls represent bromine atoms. The hydrogen bonds are shown as green dashed lines labeled with bond lengths (in Å).
FIGURE 9
FIGURE 9
(A,B) Superposition of binding poses of (−)-CG (A) and (−)-EGCG (B) withwild-type and mutant EGFR. The ligands (labeled with the ligand name) and interacting residues (gray, labeled with the residue name) are shown in stick representations. The ligand bound with wild-type EGFR is shown in blue, while the one bound with mutant EGFR is shown in yellow. The heteroatoms of the ligands and interacting residues are shown in standard colors (e.g., O-atom, red; N-atom, blue). Hydrogen bonds are shown in cyan and labeled with bond length (in Å).
FIGURE 10
FIGURE 10
(A–D) MD simulation analyses for the docked complexes of (−)-CG and (−)-EGCG with wild-type and mutant EGFR. (A) RMS deviations (RMSD) of the protein backbone with the simulation time for the protein-ligand complexes. (B) Variations in radii of gyration (Rg) with the simulation time for the protein-ligand complexes. (C) The fluctuations of the residues with the simulation time for the protein-ligand complexes. (D) Number of hydrogen bonds between the ligands and the protein with simulation time.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Abraham M. J., Murtola T., Schulz R., Pall S., Smith J. C., Hess B., et al. (2015). GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1, 19–25. 10.1016/j.softx.2015.06.001 - DOI
    1. Adhami V. M., Siddiqui I. A., Sarfaraz S., Khwaja S. I., Hafeez B. B., Ahmad N., et al. (2009). Effective prostate cancer chemopreventive intervention with green tea polyphenols in the TRAMP model depends on the stage of the disease. Clin. Cancer Res. 15 (6), 1947–1953. 10.1158/1078-0432.CCR-08-2332 - DOI - PMC - PubMed
    1. Ai Z., Liu S., Qu F., Zhang H., Chen Y., Ni D. (2019). Effect of stereochemical configuration on the transport and metabolism of catechins from green tea across Caco-2 monolayers. Molecules 24 (6), E1185. 10.3390/molecules24061185 - DOI - PMC - PubMed
    1. Albassam A. A., Markowitz J. S. (2017). An appraisal of drug-drug interactions with green tea (camellia sinensis). Planta Med. 83 (6), 496–508. 10.1055/s-0043-100934 - DOI - PubMed
    1. AlZahrani W. M., AlGhamdi S. A., Sohrab S. S., Rehan M. (2023). Investigating a library of flavonoids as potential inhibitors of a cancer therapeutic target MEK2 using in silico methods. Int. J. Mol. Sci. 24 (5), 4446. 10.3390/ijms24054446 - DOI - PMC - PubMed

Grants and funding

MR received funding for this study from the National Plan for Science, Technology, and Innovation (MAARIFAH)–King Abdulaziz City for Science and Technology (KACST), Kingdom of Saudi Arabia (Grant number: 13-BIO2478-03). The APC was funded by KACST.
-