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.