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. 2013 Apr;5(2):78-86.

Design of Small Molecules with HIV Fusion Inhibitory Property Based on Gp41 Interaction Assay

Soroush Sardari  1 , Kayhan Azadmanesh, Fereidoun Mahboudi, Asghar Davood, Ruhollah Vahabpour, Rezvan Zabihollahi, Hosna Gomari
Affiliations

Design of Small Molecules with HIV Fusion Inhibitory Property Based on Gp41 Interaction Assay

Soroush Sardari et al. Avicenna J Med Biotechnol. 2013 Apr.

Abstract

Background: Gp41 of HIV (Human Immunodeficiency Virus) is a protein that mediates fusion between viral and cellular membranes. The agent, T-20, which has been approved for HIV inhibition, can restrain Gp41 function in the fusion process; nevertheless, it has disadvantages like instability, high cost of production and injection form to be delivered twice a day.

Methods: Several molecules like NB-2 and NB-64 have been discovered that can inhibit HIV infection. These molecules were used as template compounds to design and develop more effective small molecules functioning as HIV-1 fusion inhibitors targeting Gp41. The process included in silico docking protocols using HEX and ArgusLab applications. A multisource database was created, after choosing the best molecules; they were tested in vitro for inhibitory activity by HIV-1 single-cycle model, transfected in HEK cells (293T).

Results: Computational analysis and experimental data were combined to explore molecular properties and the most potent ones were found, with the best suitable criteria for interaction with Gp41. Several examples (DAA-6, DAA-9 and DAA-12) could inhibit infection in vitro as effective as NB-2, NB-64.

Conclusion: Since disadvantages of available fusion inhibitor (T-20), it seems necessary to find similar molecules to be approved and have small size providing suitable bioactivity profile. The molecules explored in this study can be good candidates for further investigations to be used as oral HIV fusion inhibitors in the future.

Keywords: Antagonists and inhibitors; Drug design; Flow cytometry; HIV fusion inhibitors.

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Figures

Figure 1
Figure 1
The interaction energy between NHR Gp41 and the tested compounds as measured by ArgusLab applications
Figure 2
Figure 2
NB64 RMSE superimposed over with; A) DAA-6; B) DAA-9 and C) DAA-12 RMSE values are 1.7158, 2.0479 and 1.6425, respectively, which indicate that they are similar in their 3-D structures
Figure 3
Figure 3
The electrostatic surface of compounds; A) NB-64; B) DAA-6; C) DAA-9 and D) DAA-12. These compounds are similar in their electric surface
Figure 4
Figure 4
This picture shows the docking between receptor (PDB ID: 1F23) and NB-2 by Hex application. Several involving amino-acids were marked by Hex
See this image and copyright information in PMC

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