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 (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.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, Kentucky 40536, USA.
Adel
A
Hamza
Chang-Guo
CG
Zhan
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000187:drug effects; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D015195:Drug Design; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000187:drug effects; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000737:chemistry* / Q000187:drug effects; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013662:Tea / Q000737:chemistry*; D013997:Time Factors
D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; D008024:Ligands; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate