Book of Abstracts: Albany 2009
June 16-20 2009
© Adenine Press (2008)
Computational Anti-AIDS Drug Development Based on the Evidence For a Strong Attraction of the HIV-1 V3 Loop to Immunophilins
In the light of study (1), whereby the HIV-1 V3 loop is a high-affinity ligand for immunophilins present in human blood, the model of the structural complex of cyclophilin A (CycA) with the HIV-MN V3 domain was generated, and the computational design of the peptide able to mask the biologically crucial V3 segments was implemented.
To this end, the following problems were solved: (i) the NMR-based conformational analysis of the HIV-MN V3 loop was put into effect, and its low energy structure fitting the input experimental observations was determined; (ii) molecular docking of this V3 structure with the X-ray conformation of CycA was carried out, and the energy refining the simulated structural complex was performed; (iii) the inter-atomic contacts for the amino acids of the molecules forming part of the built over-molecular ensemble were specified, the types of interactions responsible for its stabilization were analyzed, and the CycA stretch that accounts for the binding to V3 was identified; (iv) the most probable 3D structure for this stretch in the unbound state was predicted, and its collation with the X-ray structure for the corresponding site of CycA was performed; (v) the potential energy function and its constituents were studied for the structural complex generated by molecular docking of the V3 loop with the CycA peptide offering the virtual molecule, which imitates the CycA segment making a key contribution to the interactions of the native protein with the HIV-1 principal neutralizing determinant; (vi) as a result of the studies above, the designed peptide was shown to be capable of the efficacious blockading the functionally crucial V3 sites; and (vii) based on the joint analysis of the evidence obtained in the present study and previously (2), the composition of the peptide cocktail presenting the promising anti-AIDS pharmacological substance was developed.
The molecules simulated here and earlier (2) by molecular modeling methods may become the first representatives of a new class of the chemicals (immunophilin-derived peptides) offering the forward-looking basic structures for the design of efficacious antiviral agents.
This study was supported by grants from the Union State of Russia and Belarus (scientific program SKIF-GRID; No. 4U-S/07-111) as well as from the Belarusian Foundation for Basic Research (project X08-003).
References and Footnotes
Alexander M. Andrianov
Inst. of Bioorganic Chemistry