Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
In Silico Discovery of Novel HIV-1 Entry Inhibitors Based on Potent and Broad Neutralizing Antibody VRC01
Computational prediction of novel HIV-1 entry inhibitors presenting peptidomimetics of broadly neutralizing antibody (bNAb) VRC01 was carried out based on the analysis of the X-ray complex of this antibody antigen-binding fragment with the HIV envelope gp120 core (Zhou et al., 2010). Using these empirical data, peptidomimetic candidates of bNAb VRC01 were identified by a public web-oriented virtual screening platform (pepMMsMIMIC) (Floris et al., 2011) and models of these candidates bound to gp120 were generated by molecular docking. At the final point, the stability of the complexes of these molecules with gp120 was estimated by molecular dynamics simulations and binding free energy calculations. The calculations identified six molecules exhibiting a high affinity to the HIV-1 gp120 protein. These molecules (Figure 1) were selected as the most probable peptidomimetics of bNAb VRC01. In a mechanism similar to that of bNAb VRC01, these compounds were predicted to block the functionally conserved regions of gp120 critical for the HIV-1 binding to cellular receptor CD4. The docked structures of the identified molecules with gp120 do not undergo substantial rearrangements during the molecular dynamics simulations, in agreement with the low values of free energy of their formation. Based on these findings, the selected compounds are considered as promising basic structures for the rational design of novel, potent, and broad-spectrum anti-HIV-1 therapeutics.
Figure 1: Two-dimensional structures of potential peptidomimetics of bNAb VRC01. The molecule codes are from the MMsINC database (Masciocchi et al., 2009).
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.
Zhou, T., Georgiev, I., Wu, X., Yang, Z.-Y., Dai, K., Finzi, A., Kwon, Y.-D., Scheid, J., Shi, W., Xu, L., Yang, Y., Zhu, J., Nussenzweig, M.C., Sodroski, J., Shapiro, L., Nabel, G.J., Mascola, J.R. & Kwong, P.D. (2010). Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science, 329, 811-817.
Alexander M. Andrianov1
1 Institute of Bioorganic Chemistry