Epigallocatechin Gallate (EGCG) – A Novel Covalent NF- κB Inhibitor: Structural and Molecular Characterization

Tea contains antioxidant catechins thought to exert health-promoting protective effects against conditions involving chronic inflammation, such as cardiovascular diseases. The most abundant catechin in tea is Epigallocatechin Gallate (EGCG), thought to be a key contributor to tea’s health-promoting actions. EGCG exerts protective cardiovascular effects via its antioxidant, antiinflammatory, hypolipidemic, anti-thrombogenic, and anti-hypertensive actions. Because EGCG inhibits the strong proinflammatory gene-inducing transcription factor NF-κB, we analyzed the chemical and molecular details of the mechanism by which EGCG mediates NF-κB inhibition. We quantified and mapped key parameters of its chemical reactivity including its electrophilic Fukui ƒ+ function, in silico covalent binding, and identified its frontier Molecular Orbitals (MOs) and nucleophilic susceptibility. These physical and chemical reactivity parameters revealed that the bond-forming MOs are distributed on the B ring of the EGCG oxidized state with nucleophilic susceptibility, and that this B ring has properties that favor participating in a Cys-alkylating 1,4-addition reaction. Molecular modeling and docking analysis further revealed that EGCG bonds covalently with Cys-38 of NF-κB-p65, and thereby inhibits its DNA binding ability. We also generated a model pharmacophore based on the EGCG-NF-κB complex. We conclude that EGCG covalently binds to NF-κB-p65 and inhibits it by abolishing its DNA binding, by chemical mechanisms that may inform design of EGCG derivatives as novel anti-inflammatory agents.