Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Click Chemistry In Silico and Molecular Simulation Studies to Identify Novel HIV-1 Entry Inhibitor Scaffolds Targeting CD4-Binding Site of the Envelope gp120 Protein

In silico design of novel potential HIV-1 entry inhibitors able to block CD4-binding site of the envelope gp120 protein was carried out based on the click chemistry concept. In doing so, a Drug-Like subset of the ZINC database (Irwin, Sterling, Mysinger, Bolstad, & Coleman, 2012) was screened by the DataWarrior program to generate two virtual molecular libraries. Library 1 comprised small molecules with an azide group or an alkyne group and aromatic fragments critically important for the HIV-1 attachment to cellular receptor CD4. In library 2, all low-molecular compounds with an azide group or an alkyne group were collected. The modular units from libraries 1 and 2 were then used as reagents to mimic the click chemistry reaction of azide-alkyne cycloaddition by the AutoClickChem program (Durrant & McCammon, 2012). This resulted in a set of 1 655 301 hybrid molecules. 294 378 compounds that fully satisfied Lipinski's “rule of five” (Lipinski, Lombardo, Dominy, & Feeney, 2001) were further screened by high-throughput docking and molecular dynamics simulations to evaluate the affinity of their binding to the target protein. As a result, five top hits (Figure 1) that exhibited strong attachment to the two well-conserved hotspots of the gp120 CD4-binding site were selected for the final analysis. In analogy to CD4, the identified compounds form hydrogen bonds with Asp-368gp120 and multiple van der Waals contacts with the gp120 residues that bind to Phe-43CD4, resulting in destruction of the critical interactions of gp120 with Phe-43CD4 and Arg-59CD4. The complexes of the CD4-mimetic candidates with gp120 show relative conformational stability within the molecular dynamics simulations and expose the high percentage occupancies of intermolecular H-bonds, in line with the low values of binding free energy. In this context, the identified compounds are considered as good scaffolds for the development of new functional antagonists of viral entry with broad HIV-1 neutralization.


Figure 1: Chemical structures of the potential HIV-1 entry inhibitors. The atoms of hydrogen, oxygen and nitrogen forming hydrogen bonds in the dynamic structures of the complexes between the ligands and HIV-1 gp120 protein are numbered.


    Durrant, J.D. & McCammon, J.A. (2012). AutoClickChem: Click сhemistry in silico. PLoS Comput. Biol., 8: e1002397.

    Irwin, J.J., Sterling, T., Mysinger, M.M., Bolstad, E.S. & Coleman, R.G. (2012). ZINC: A free tool to discover chemistry for biology. J. Chem. Inf. Model., 52, 1757–1768.

    Lipinski, C.A., Lombardo, F., Dominy, B.W. & Feeney, P.J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 46, 3–26.

Alexander M. Andrianova
Grigory I. Nikolaevb,,
Yuri V. Kornoushenkoa
Alexander V. Tuzikovb

a Institute of Bioorganic Chemistry
National Academy of Sciences of Belarus
220141 Minsk, Belarus
b United Institute of Informatics Problems
National Academy of Sciences of Belarus
220012 Minsk, Belarus

Ph: (+37517) 264-82-63
Email: alexande.andriano@yandex.ru