This study was performed to develop a quantitative structure–activity relationship (QSAR) model of the biological activity of indole glyoxamide derivatives as an inhibitor of the interaction between human immunodeficiency virus (HIV) glycoprotein gp120 and host cell CD4 receptors. In present study, forty different compounds were selected as a sample set. Combinations of multiple linear regressions (MLR), genetic algorithms (GA) and artificial neural networks (ANN) were then utilized to construct the QSAR models. These models were also utilized to nonlinearly select the most efficient subsets of descriptors in a cross-validation procedure for nonlinear log (1/EC50) prediction. The obtained results using GA-ANN were compared with MLR-MLR and MLR-ANN models. The obtained models showed high prediction ability with root mean sum square error (RMSE) of 0.99, 0.91 and 0.67 for MLR, MLR-ANN and GA-ANN models, respectively (N=40).
Keywords: Genetic algorithm; artificial neural network; multiple linear regressions; HIV;
Quantitative Structure – Activity Relationship;
The process of human immunodeficiency virus-1( HIV-1) entry into host cells, offers considerable potential for therapeutic intervention, with viral entry proceeding through multiple sequential steps involving attachment, coreceptor binding, and fusion (8, 13). The early step of viral entry into the host cell is accomplished through binding of the viral envelope glycoprotein complex gp160 to the cellular receptor, CD4. This attachment is followed by conformational changes of the gp160 external glycoprotein portion, gp120, which facilitates the second step involving binding to a cellular co-receptor, usually the chemokine receptor CCR5 or CXCR4. Co-receptor binding in turn facilitates a large conformational change and initiates the final entry event which leads to dissociation of gp120 from gp41, the virus membrane-spanning protein that mediates the fusion of the virus with the host cell. The discovery of indole-3-glyoxamide derivatives (such as BMS-378806 and BMS-488043) has been described as the first small molecule inhibitors of the gp120-CD4 interaction (HIV-1 attachment inhibition) that demonstrate potent antiviral activity in cell culture. These compounds, of which the 4-fluoro derivative is prototypical, appear to act by stabilizing a specific conformation of gp120 that is poorly recognized by CD4 [1-5]. However, under certain circumstances, compounds of this class have been shown to form a ternary complex with gp-120 and CD4 and interfere with the CD4-induced exposure of the gp 41 heptad repeats, providing a potential additional mode of action [1-5]. Activity of attachment inhibitors is independent of human chemokine co-receptor binding and persists irrespective of viral tropism or host cell phenotype (5, 7, 10). Since attachment inhibitors target a viral protein rather than a host chemokine receptor, they are not expected to impact...