Evaluation of the Inhibitory Potential of Apigenin and Related Flavonoids on Various Proteins Associated with Human Diseases Using AutoDock

Abstract

We used molecular docking to determine the binding energy and interactions of apigenin and 16 related flavonoids, with 24 distinct proteins having diverse biological functions. We aimed to identify potential inhibitors of these proteins and understand the structural configurations of flavonoids impacting their binding energy. Our results demonstrate that apigenin exhibits high binding energies (a surrogate for binding affinity or inhibitory potential) to all tested proteins. The strongest binding energy was -8.21 kcal/mol for p38 mitogen-activated protein kinases, while the weakest was -5.34 kcal/mol for cyclin-dependent kinase 4. Apigenin and many other flavonoids showed high binding energies on xanthine oxidase (1.1-1.5 fold of febuxostat) and DNA methyltransferases (1.1-1.2 fold of azacytidine). We uncovered high binding energies of apigenin and certain flavonoids with mutated Kirsten rat sarcoma viral oncogene homolog at G12D (KRAS G12D), G12V, and G12C. Consequently, apigenin and certain flavonoids have the potential to effectively inhibit pan-KRAS oncogenic activity, not just on specific KRAS mutations. Apigenin and certain flavonoids also have high binding energies with aromatase (involved in estrogen production) and bacterial infections, i.e., DNA gyrase B and 3R-hydroxy acyl-ACP dehydratase (FABZ). Our findings are pivotal in identifying specific flavonoids that can effectively inhibit targeted proteins, paving the way for the development of innovative flavonoid-based drugs.

Keywords: KRAS mutations; apigenin; bacterial infections; flavonoids; molecular docking; oxidative stress and inflammation.

Figure 1

The 3D images illustrate the interactions between three compounds: apigenin (green), genistein (pink), and quercetin (yellow) with a receptor involved in oxidative stress, specifically XO (PDB: 3ETR). The images highlight hydrogen bonds (represented by dotted blue lines) formed between the ligands (with oxygen molecules shown in red and hydrogen molecules in white) and the amino acids located in the active site of the XO receptor.

Figure 2

The 3D images illustrate the interactions between apigenin (in green), genistein (in pink), and quercetin (in yellow) with a receptor involved in inflammation, i.e., COX-2 (PDB: 3NT1). The images highlight hydrogen bonds formed between the ligands (represented by the red oxygen molecules and white hydrogen molecules) and the amino acids located in the active site of the COX-2 receptor.

Figure 3

The 3D images illustrate the interactions between apigenin (in green), genistein (pink), and quercetin (yellow) with receptors involved in EGFR and KRAS pathways: EGFR T790M/V948R (PDB: 6Z4B), KRAS G12D (PDB: 6GJ8), and KRAS G12V (PDB: 8AZZ). The images depict hydrogen bonds (dotted blue lines) between the ligand (oxygen molecules in red and hydrogen molecules in white) and the amino acids located in EGFR and KRAS.

Figure 4

The 3D images illustrate the interaction and binding energies of apigenin (green), genistein (pink), and quercetin (yellow) with the BRAF V599E (PDB: 1UWJ) which is involved in the RAF/MEK/ERK signaling pathway. The images depict hydrogen bonds (represented by dotted blue lines) between the ligand (with oxygen molecules in red and hydrogen molecules in white) and amino acids located in the BRAF.

Figure 5

The 3D images show examples of the interaction of the molecular docking and binding energies between apigenin (green), genistein (pink), and quercetin (yellow) with a receptor involved in the PI3K, AKT, and mTOR pathway i.e., mTOR (PDB: 4JT6). The images show hydrogen bonds (dotted blue lines) between the ligand (oxygen molecules in red and hydrogen molecules in white) and amino acids in the mTOR active sites.

Figure 6

The 3D images illustrate the interaction between the molecular docking and binding energies of three compounds: apigenin (green), genistein (pink), and quercetin (yellow) with the cyclin-dependent kinases 6 (CDK6) receptor (PDB: 5L2T). The images highlight the hydrogen bonds (represented by dotted blue lines) between the ligand (with oxygen molecules in red and hydrogen molecules in white) and amino acids within one of the active sites of CDK6.

Figure 7

The 3D images illustrate the interaction of the molecular docking and binding energies between three compounds: apigenin (green), genistein (pink), and quercetin (yellow) with a receptor involved in epigenetics, specifically HDAC2 (PDB: 4LXZ). The images show hydrogen bonds, depicted as dotted blue lines between the ligand (oxygen molecules in red and hydrogen molecules in white) and amino acids within one of the active sites of HDAC2.

Figure 8

The 3D images illustrate the interaction of the molecular docking and binding energies between apigenin (green), genistein (pink), and quercetin (yellow) with a receptor involved in bacterial infection, specifically DNA Gyrase B (PDB: 6F86). The images highlight hydrogen bonds, represented by dotted blue lines, between the ligands (with oxygen molecules in red and hydrogen molecules in white) and amino acids located in one of the active sites of Gyrase B.