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

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 (ΔG_bind = -5.5 kcal/mol, K _d = 94 μM) is in excellent agreement with available experimental data suggesting IC₅₀ ≈ 100 μM 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.