Virtual screening and identification of potential HIV-1 inhibitors based on the cross-reactive neutralizing antibody N6
https://doi.org/10.29235/1561-8323-2019-63-4-445-456
Abstract
Six potential peptidomimetics of the cross-reactive neutralizing anti-HIV-1 antibody N6 that are able to mimic the pharmacophoric features of this immunoglobulin by specific and effective interactions with the CD4-binding site of the viral gp120 protein were identified by virtual screening and molecular modeling. The key role in the interaction of these compounds with gp120 is shown to play multiple van der Waals contacts with conserved residues of the gp120 Phe43 cavity critical for the HIV binding to cellular receptor CD4, as well as hydrogen bonds with Asp-368gp120 that increase the chemical affinity without activating unwanted allosteric effect. According to the data of molecular dynamics, the complexes of the identified ligands with gp120 are energetically stable and show the lower values of binding free energy compared with the HIV-1 inhibitors NBD-11021 and DMJ-II-121 used in the calculations as a positive control. The identified compounds may be involved in the design of novel antiviral drugs presenting HIV-1 inhibitors that block the early stages of the development of HIV infection.
Keywords
HIV-1,
gp120 protein,
antibody N6,
HIV-1 entry inhibitors,
virtual screening,
molecular docking,
molecular dynamics,
anti-HIV drugs
Supporting agencies: The study was supported by grants from the Belarusian Foundation for Fundamental Research (project X18КИ-002) and the National Natural Science Foundation of China (project 84630090) within the cooperation and exchange Program.
About the Authors
Alexander M. Andrianov
Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus
Belarus
Belarus
Andrianov Alexander Mikhailovich – D. Sc. (Chemistry), Chief researcher
5/2, kuprevich Str., 220141, Minsk
Gregory I. Nikolaev
United Institute of Informatics Problems of the National Academy of Sciences of Belarus
Belarus
Belarus
Nikolaev Grigory Igorevich – Postgraduate student
6, Surganov Str., 220012, Minsk
Yuri V. Kornoushenko
Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus
Belarus
Belarus
Kornoushenko Yuri Valerievich – Ph. D. (Chemistry), Senior researcher
5/2, kuprevich Str., 220141, Minsk
Jinghe Huang
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan University
China
China
Jinghe Нuang – Professor
Shanghai
Shibo Jiang
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan University
China
China
Shibo Jiang – Professor
Shanghai
Alexander V. Tuzikov
United Institute of Informatics Problems of the National Academy of Sciences of Belarus
Belarus
Belarus
Tuzikov Alexander Vasilievich – Corresponding Member, D. Sc. (Physics and Mathematics), Professor, General Director
6, Surganov Str., 220012, Minsk
References
1. Arts E. J., Hazuda D. J. HIV-1 antiretroviral drug therapy. Cold Spring Harbor Perspectives in Medicine, 2012, vol. 2, no. 4, pp. a007161. https://doi.org/10.1101/cshperspect.a007161
2. kumari G., Singh R. k. Highly active antiretroviral therapy for treatment of HIV/AIDS patients: current status and future prospects and the Indian scenario. HIV & AIDS Review, 2012, vol. 11, no. 1, pp. 5–14. https://doi.org/10.1016/j.hivar.2012.02.003
3. Wang H.-B., Mo Q.-H., yang Z. J. HIV vaccine research: The challenge and the way forward. Journal of Immunology Research, 2015, vol. 2015, art. 503978. https://doi.org/10.1155/2015/503978
4. Barouch D. H. Challenges in the development of an HIV-1 vaccine. Nature, 2008, vol. 455, no. 7213, pp. 613–619. https://doi.org/10.1038/nature07352
5. Mann J. k., Ndung’u T. HIV-1 vaccine immunogen design strategies. Virology Journal, 2015, vol. 12, no. 1, pp. 3. https://doi.org/10.1186/s12985-014-0221-0
6. Huang J., kang B. H., Ishida E., Zhou T., Griesman T., Sheng Z., Wu F., Doria-Rose N. A., Zhang B., McKee K., O’Dell S., Chuang G. y., Druz A., Georgiev I. S., Schramm C. A., Zheng A., Joyce M. G., Asokan M., Ransier A., Darko S., Migueles S. A., Bailer R. T., Louder M. k., Alam S. M., Parks R., kelsoe G., Von Holle T., Haynes B. F., Douek D. C., Hirsch V., Seaman M. S., Shapiro L., Mascola J. R., kwong P. D., Connors M. Identifcation of a CD4-binding-site antibody to HIV that evolved nearpan neutralization breadth. Immunity, 2016, vol. 45, no. 5, pp. 1108–1121. https://doi.org/10.1016/j.immuni.2016.10.027
7. Sunseri J., koes D. R. Pharmit: interactive exploration of chemical space. Nucleic Acids Research, 2016, vol. 44, pp. W442–W448. https://doi.org/10.1093/nar/gkw287
8. Alhossary A., Handoko S. D., Mu y., kwoh C. k. Fast, accurate, and reliable molecular docking with QuickVina 2. Bioinformatics, 2015, vol. 31, no. 13, pp. 2214–2216. https://doi.org/10.1093/bioinformatics/btv082
9. Curreli F., kwon y. D., Zhanga H., Scacalossi D., Belov D. S., Tikhonov A. A., Andreev I. A., Altieric A., kurkin A. V., kwong P. D., Debnath A. k. Structure-based design of a small molecule CD4-antagonist with broad spectrum anti-HIV-1 activity. Journal of Medicinal Chemistry, 2015, vol. 58, no. 17, pp. 6909–6927. https://doi.org/10.1021/acs.jmedchem.5b00709
10. Courter J. R., Madani N., Sodroski J., Schön A., Freire E., kwong P. D., Hendrickson W. A., Chaiken I. M., LaLonde J. M., Smith A. B. Structure-based design, synthesis and validation of CD4-mimetic small molecule inhibitors of HIV-1 entry: Conversion of a viral entry agonist to an antagonist. Accounts of Chemical Research, 2014, vol. 47, no. 4, pp. 1228–1237. https://doi.org/10.1021/ar4002735
11. Case D. A., Betz R. M., Cerutti D. S., Cheatham T. E., Darden T. A., Duke R. E., Giese T. J., Gohlke H., Goetz A. W., Homeyer N., Izadi S., Janowski P., kaus J., kovalenko A., Lee T. S., LeGrand S., Li P., Lin C., Luchko T., Luo R., Madej B., Mermelstein D., Merz k. M., Monard G., Nguyen H., Nguyen H. T., Omelyan I., Onufriev A., Roe D. R., Roitberg A., Sagui C., Simmerling C. L., Botello-Smith W. M., Swails J., Walker R. C., Wang J., Wolf R. M., Wu X., Xiao L., kollman P. A. AMBER 2016. San Francisco, 2016.
12. kwong P. D., Wyatt R., Robinson J., Sweet R. W., Sodroski J., Hendrickson W. A. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature, 1998, vol. 393, no. 6686, pp. 648–659. https://doi.org/10.1038/31405
13. Olshevsky U., Helseth E., Furman C., Li J., Haseltine W., Sodroski J. Identifcation of individual humanimmunodefciency-virus type-1 gp120 amino-acids important for CD4 receptor-binding. Journal of Virology. 1990, vol. 64, no. 12, pp. 5701–5707.
14. Liu y., Schön A., Freire E. Optimization of CD4/gp120 inhibitors by thermodynamic-guided alanine-scanning mutagenesis. Chemical Biology and Drug Design, 2013, vol. 81, no. 1, pp. 72–78. https://doi.org/10.1111/cbdd.12075
15. Myszka D. G., Sweet R. W., Hensley P., Brigham-Burke M., kwong P. D., Hendrickson W. A., Wyatt R., Sodroski J., Doyle M. L. Energetics of the HIV gp120-CD4 binding reaction. Proceedings of the National Academy of Sciences of the United States of America, 2000, vol. 97, no. 16, pp. 9026–9031. https://doi.org/10.1073/pnas.97.16.9026
Review
Views: 1312
Email this article 