Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Virtual Screening of Novel Anti-HIV-1 Agents Targeting CD4-Binding Site of the Envelope GP120 Protein
Targeting the HIV-1 gp120-CD4 interface has become a cutting-edge approach in the current anti-AIDS drug discovery. Many small molecules that inhibit the interaction between CD4 and HIV-1 gp120 have been developed. However, due to various reasons such as solubility, drug toxicity and drug resistance, these inhibitors have failed to be clinically useful. As such, the identification of novel compounds that block the HIV-1 CD4-binding site is still a research area of considerable interest.
In this study, computer-aided search for novel anti-HIV agents that are able to mimic cellular receptor CD4 was carried out using the pepMMsMIMIC virtual screening platform (Floris et al., 2011) associated with the MMsINC database (Masciocchi et al., 2009). In doing so, the X-ray data on the CD4 amino acid residues responsible for specific interactions with gp120 (Kwong et al., 1998) were used as the input data for pepMMsMIMIC. Potential anti-HIV-1 activity of the CD4 peptidomimetic candidates found in the MMsINC database was evaluated by molecular docking, molecular dynamics (MD) simulations and binding free energy calculations. The MD simulations of the twenty top-ranking docked complexes between the CD4 potential peptidomimetics and gp120 revealed five molecules that exposed negative binding free energy values. These molecules were therefore selected for the final analyses. Visualization of the docked structures of the identified compounds with the HIV-1 gp120 core (Kwong et al., 1998) shows that these molecules partially mimic CD4 by specific interactions with the Phe-43 cavity of gp120 critical for the HIV-1 binding to CD4. An insight into the MD structures of these complexes indicates that intermolecular hydrogen bonds and van der Waals interactions involving such functionally important residues of gp120 as Asp-368, Glu-370, Gly-429, Arg-456, Glu-466, Thr-467 and Gly-473 (Kwong et al., 1998) dominate the binding. Finally, the analyzed complexes are stable within the MD simulations, exposing the low values of free energy of their formation.
Thus, the molecular modeling data suggest that the selected compounds may be able to neutralize different HIV-1 modifications and, therefore, present potential broad-spectrum HIV-1 entry inhibitors that should be subject to testing for anti-HIV-1 activity against various viral isolates.
Kwong, P.D., Wyatt, R., Robinson, J., Sweet, R.W., Sodroski, J. & Hendrickson, W.A. (1998). Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature, 393, 648-659.
Masciocchi, J., Frau, G., Fanton, M., Sturlese, M., Floris, M., Pireddu, L., Palla, P., Cedrati, F., Rodriguez-Tome, P. & Moro, S. (2009). MMsINC: a large-scale chemoinformatics database. Nucleic Acids Research, 37, D284-D290.
Alexander M. Andrianov1
1 Institute of Bioorganic Chemistry