## 3 Physico-Chemical Rational of the Styrylquinoline-Integrase Interaction
### Comparative molecular field analysis and docking studies  
Initial modelling studies were conducted using the Rous sarcoma virus (RSV) integrase core domain [40,41]. _Ab initio_ studies were first performed in order to elucidate the conformation and charge distribution of **77q** (Table 7). The _s-trans_ conformation as usually represented in the schemes was found the most stable. The same conformation was observed in the crystal structure [43]. However, the _s-cis_ confirmation was found to be higher in energy by only 0.3 kcal/mol. Thus, we can assume that considerable flexibility around this bond exists in biological medium. Docking of the styrylquinoline **77q** shows that the inhibitor binds closely to the Mg\({}^{2+}\) cation making contacts with the D64, N122, N149, Q153, N160 residues [40,41]. In a more recent work [44], compound **35** (Scheme 3) was docked on the HIV-1 IN catalytic core. After rigid docking and minimization, the best target-drug complexes were selected according to their interaction energies (coulombic and Van der Waals). Three main cluster sites were identified. The contacting residues of cluster 1 overlap the catalytic triad (Figure **5a**). Cluster 2 is actually made of a succession of overlapping sites and is spread over a large  
Figure 4: Structures of **3b** and X-ray structures of magnesium complex **3b-Mg**. DFT electrostatic potential features of putative magnesium complexes **3b-Mg A**, **3b-Mg B**. Grey and black isosurfaces correspond to +0.20 and -0.10 a.u., respectively. The arrows indicate the local minimum values of the electrostatic potential.  
region of the protein surface (Figure **5b**) whereas a little number of conformations forms the cluster 3 (not shown). As expected, the negatively charged drug bound to lysine-rich regions. Residues K156 and K159 Q148 and S119 in cluster 1 have been previously found to be involved in DNA binding [45, 46, 47]. In contrast, no residues from cluster 2 are known to be essential for DNA binding. In conclusion, from computational simulations, it seems that cluster 1 is the primary binding site for SQLs as already observed with the RSV core domain. This cluster, which corresponds to one of the two proposed DNA-binding sites, contains the catalytic triad and several key residues for DNA-binding [48].  
Using a fluorescence anisotropy-based DNA-binding assay it was confirmed that SQLs prevent recognition of viral by IN, demonstrating that the 3'-processing inhibitory effect is in fact due to the ability to impair DNA binding by competitive inhibition. This mechanism strongly differs from the one of INSTIs which do not bind efficiently to the active site of the free IN but display a strong affinity for the IN/viral DNA complex [31, 49].  
Furthermore, attempts were made to obtain a Comparative Molecular Field Analysis (CoMFA) model to predict the activity and the rational binding mode of styrylquinoline derivatives to IN [42]. (CoMFA) was performed to analyze three-dimensional quantitative structure-activity relationship (3D-QSAR) of styrylquinoline derivatives. The stability of 3 DQSAR models was proved by the analysis of cross-validated and non-cross-validated methods.