Molecular docking simulations of various aryl amide derivatives of Imidazo[1,5-a]pyridine-1,2,4-thiadiazoles against EGFR protein

The nitrogenous fused hetero-aromatic scaffolds are found broadly in biological and natural products motifs, these are considered as significant core blocks in medicinal and material field.^1-3 In particularly, imidazo[1,5-a]pyridine are most unique class of nitrogen atom having fused bicyclic heterocyclic molecules and are played a vital role in synthetic and medicinal chemistry.^4-6  They possessed a broad spectrum of biological activities including antibacterial,⁷ thromboxane synthetase inhibitors,⁸ inhibitors of aromatase,⁹ antiviral,¹⁰ positive inotropic agents,¹¹ anti-tuberculosis,¹² antifungal,¹³ antiprotozoal,¹⁴ anti-inflammatory,¹⁵ AChE and BChE inhibition,¹⁶ anticandidosic activity,¹⁷ anti-plasmodial,¹⁸ protein-kinase inhibitor,¹⁹ and vascular endothelial growth factor (VEGF)-receptor²⁰ activities.

RESULTS AND DISCUSSION:

Based on the above literature, we designed the following aryl amide derivatives of Imidazo [1,5-a]pyridine-1,2,4-thiadiazoles.

Figure 1: Structure of aryl amide derivatives of Imidazo[1,5-a]pyridine-1,2,4-thiadiazoles

In this current docking study, we focused on key cancer-related proteins that are implicated in the progression of various cancer types. We chose EGFR, for molecular docking due to their pivotal roles in cancer pathology including tumor growth, metastasis, and angiogenesis. This protein are well-established therapeutic targets in cancer treatment, making them ideal candidates for exploring potential therapeutic compounds.

Binidng energy and interaction summary of compounds with human EGFR TKD

Molecular interaction summary of top compounds with Human EGFR TKD was shown in table 1. The 2D NMR structures of all compounds were shown in figure 2. Protein ligand complexes representing the binding modes of 1a, 1b, 1c, 1f, 1j compounds and and Erlotinib and interacting residues in the active site in human human EGFR TKD B) Pharmacophore features of compounds along with Erlotinib were shown in figure 3.

 

 

Figure 2: 2D molecular representation of interactions of compounds A) 1a, B) 1b, C) 1c, D) 1f, E) 1j F) Erlotinib with the active site residues of the EGFR. Interactions were displayed as color coded dashed lines, green lines indicated the H–bonds.

 

 

Figure 3: Protein ligand complexes representing the binding modes of 1a, 1b, 1c, 1f, 1j compounds and and Erlotinib and interacting residues in the active site in human human EGFR TKD B) Pharmacophore features of compounds along with Erlotinib  (Pharmacophore features color coding include: Purple spheres-Aromatic, Green spheres-Hydrophobic, Orange spheres-HBD and White spheres-HBA).

 

 

Figure 4: The Brain Or Intestinal Estimated Permeation (BOILED-Egg) method illustrates the absorption, blood-brain barrier (BBB) permeation, and substrate selectivity for P-glycoprotein (PGP) of compounds 1a, 1b, 1c, 1f and 1j. Blue indicates substrate of P-glycoprotein (PGP), while red represents non-substrate of PGP.

The ADME predictions highlight the need for optimization of the compounds, particularly due to the significant challenge posed by the poor solubility of all the compounds, along with the low gastrointestinal absorption observed for compounds 1a and 1b.

Compounds 1c, 1f, and 1j demonstrate high gastrointestinal (GI) absorption, while all compounds were predicted not to cross the blood-brain barrier (BBB). According to the BOILED-Egg model in Figure 4, all the compounds are identified as substrates of P-glycoprotein (P-gp). This characteristic may affect their bioavailability and distribution, as P-gp actively transports substances out of cells, potentially reducing their intracellular concentrations.

Compounds 1c, 1f, and 1j adhere to Lipinski's Rule of Five, while compounds 1a and 1b slightly deviate due to their molecular weight exceeding 500. Additionally, these compounds are predicted to inhibit several CYP isoforms, including CYP2C19, CYP2C9, CYP3A4, and CYP2D6.

Toxicity assessment using the pkCSM webserver predicts that all the compounds under investigation are hERG II inhibitors, but they do not show signs of hepatotoxicity, mutagenicity, or skin sensitization. hERG II inhibition suggests a potential risk of cardiac issues, such as QT prolongation and arrhythmias. To mitigate these risks, it is crucial to optimize the compounds to enhance their therapeutic efficacy and safety profile.

CONCLUSION

In conclusion, these compounds also demonstrated stronger binding affinities with the EGFR target compared to the co-crystallized inhibitor Erlotinib, which has a binding energy of -6.9 kcal/mol. All compounds exhibited higher binding energies in the range of -7.8 to -8.5 kcal/mol, with compound 19f showing the highest affinity at -8.5 kcal/mol, followed closely by compound 19j at -8.3 kcal/mol.

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