Book of Abstracts: Albany 2011

category image Albany 2011
Conversation 17
June 14-18 2011
©Adenine Press (2010)

Computer-Aided Design of Novel HIV-1 Entry Inhibitors, Their Synthesis and Trials: Glycolipids Against the Envelope gp120 V3 Loop

The HIV-1 V3 loop plays a central role in the biology of the HIV-1 envelope glycoprotein gp120 as a principal target for neutralizing antibodies, and as a major determinant in the switch from the non-syncytium-inducing to the syncytium-inducing form of HIV-1 that is associated with accelerated disease progression. HIV-1 cell entry is mediated by the sequential interactions of gp120 with the receptor CD4 and a co-receptor, usually CCR5 or CXCR4, depending on the individual virion. The V3 loop is critically involved in this process. Because of the exceptional role of the V3 loop in the viral neutralization and cell tropism, one of the actual problems is that of identifying chemical compounds able to block this functionally crucial site of gp120. According to empirical observations, glycolipid β-galactosylceramide (β-GalCer) forming on the surface of some susceptible host cells the primary receptor for HIV-1 alternative to CD4 exhibits a strong attraction to the V3 loop and, for this reason, may be involved in anti-HIV-1 drug studies. In the light of these observations, the use of bioinformatics tools for imitating the process of making the V3/glycolipid complexes may provide a structural rationale for the design of efficient blockers of the functionally important V3 sites.

The objects of this study were to generate the 3D structure model for the complex of V3 with β-GalCer and, based on the calculation data, to design its water soluble analogs that could efficiently mask the HIV-1 V3 loop followed by their synthesis and medical trials. To this effect, the following problems were solved: (i) 3D structures for the consensus amino acid sequences of the HIV-1 subtypes A and B V3 loops were computed by homology modeling and simulated annealing; (ii) spatial structures of β-GalCer, as well as of a series of its modified forms were determined by quantum chemistry and molecular dynamics simulations; (iii) supramolecular ensembles of these glycolipids with V3 were built by molecular docking methodology and energy characteristics describing their stability were estimated by molecular dynamics computations; (iv) synthesis of β-GalCer derivatives that, according to the designed data, give rise to the stable complexes with V3 was performed, and (v) testing of these compounds for antiviral activity was carried out. From the structural data obtained, the Phe and Arg/Gln amino acids of the gp120 immunogenic crest were revealed to play a key role in forming the complexes of glycolipids with V3 by specific interactions with the galactose residue and sphingosine base respectively. And at the same time, the sugar hydroxyl groups form the H-bonds with the nearby polar atoms of the V3 backbone. Two water soluble analogs of β-GalCer were also found to display a high affinity to V3 close to that of the native glycolipid. This inference results from the values of binding free energy evaluated for the calculated structures and coincides with the experimental data on the complexes of gp120 with β-GalCer. The above theoretical findings are in keeping with those of medical trials of the synthesized molecules, which testify to their anti-HIV-1 activity against the virus subtypes A and B isolates.

As a matter of record, the molecules constructed here are supposed to present the promising basic structures for the rational design of novel potent HIV-1 entry inhibitors that could neutralize the majority of circulating indigenous strains. For some of the details of the methodologies of current drug designs employed here please consult the full length research articles (1-4).


  1. A. M. Andrianov, I. V. Anishchenko, J. Biomo.l Struct. Dyn. 27, 179-193 (2009).
  2. A. M. Andrianov, J. Biomol. Struct. Dyn. 26, 445-454 (2009).
  3. T. T. Chang, H.J. Huang, K. J. Lee, H. W. Yu, H.Y. Chen, F.J. Tsai, M.F. Sun, C. Y. C. Chen, J Biomol Struct Dyn 28, 309-321 (2010).
  4. A. K. Kahlon, S. Roy, A. Sharma, J Biomol Struct Dyn 28, 201-210 (2010).

Alexander M. Andrianov1
Ivan V. Anishchenko2
Mikhail A. Kisel
Vasiliy A. Nikolayevich1
Vladimir F. Eremin3
and Alexander V. Tuzikov2

1Institute of Bioorganic Chemistry National Academy of Sciences of Belarus Kuprevich Street 5/2 220141 Minsk, Republic of Belarus
2 United Institute of Informatics Problems National Academy of Sciences of Belarus Surganov Street 6 220012 Minsk, Republic of Belarus
3The Republican Research and Practical Center for Epidemiology and Microbiology Filimonova Street 23 220114 Minsk, Republic of Belarus