How Can (−)-Epigallocatechin Gallate from Green Tea Prevent HIV-1 Infection? Mechanistic Insights from Computational Modeling and the Implication for Rational Design of Anti-HIV-1 Entry Inhibitors

Abstract

Possible inhibitors preventing human immunodeficiency virus type 1 (HIV-1) entry into the cells are recognized as hopeful next-generation anti-HIV-1 drugs. It is highly desirable to develop a potent inhibitor blocking binding of glycoprotein CD4 of the cell with glycoprotein gp120 of HIV-1, because the gp120-CD4 binding is the initial step of HIV-1 entry into the cells. It has been recently reported that (-)-epigallocatechin gallate (EGCG) from green tea is an inhibitor blocking gp120-CD4 binding. But the inhibitory mechanism remains unknown. For understanding the inhibitory mechanism, extensive molecular docking, molecular dynamics simulations, and binding free-energy calculations have been performed in this study to predict the most favorable structures of CD4-EGCG, gp120-CD4, and gp120-CD4-EGCG binding complexes in water. The results reveal that EGCG binds with CD4 in such a way that the calculated binding affinity of gp120 with the CD4-EGCG complex is negligible. So, the favorable binding of EGCG with CD4 can effectively block gp120-CD4 binding. The calculated CD4-EGCG binding affinity (DeltaG(bind) = -5.5 kcal/mol, K(d) = 94 microM) is in excellent agreement with available experimental data suggesting IC(50) approximately 100 microM for EGCG-blocking CD4-gp120 binding. These results and insights provide a rational basis for future design of novel, more potent inhibitors to block gp120-CD4 binding.

A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells

“…The simulated protein-ligand binding structures were used for binding free energy calculations. The most favorable structure of the ligand binding with Hsp90 had a binding energy of -18.8 kcal/mol, excluding the entropic contribution (19). The in silico model of the Hsp90-celastrol binding and the subsequent molecular dynamic simulation showed that celastrol formed a favorable complex with Hsp90 in a binding site distinct from the ATP-binding pocket (Fig.…”

Epigallocatechin Gallate Inactivates Clinical Isolates of Herpes Simplex Virus

“…EGCG binds to a wide variety of proteins, especially to nonglobular extended proteins and particularly to proteins with a high proline content (10,11,18,24,31,33,37,44). EGCG inhibits the binding of HIV envelope glycoprotein gp120 to the CD4 receptor (15,20,52) and inhibits influenza virus replication by specific interaction with the hemagglutinin envelope glycoprotein and potentially altering the physical properties of the viral envelope (29,40). HSV encodes 11 or 12 glycoproteins, and there is a large body of evidence that 4 of these glycoproteins, gD, gB, and gH/gL, are required for virion entry into cells (4).…”

Potential Therapeutic Molecular Targets for Nasopharyngeal Carcinoma

“…EGCG has been reported to possess several biochemical and pharmacological properties, which include anti-HIV and HCV infection activity (49,94,318,325), reduction of Sjögren's syndrome in murine models (83,110), prevention of Alzheimer's and Parkinson's diseases (203), anti-obesity effects on mice and humans (41,319), anti-oxidant activity (75,104,293,348), and anti-neoplastic activity (135,262). The cancer-preventive effects of EGCG have been proposed to suppress the transformative, hyperproliferative, and inflammatory processes that are involved in carcinogenesis (288).…”