Two structural components are necessary for integrase binding: a hydrophobic benzyl moiety that buries into a highly hydrophobic pocket near the active site; and chelating triad that binds with two Mg ions in a rather hydrophilic region, anchoring the inhibitor onto the protein surface (see figure 3). In fact, all potent integrase inhibitors possess a substituted benzyl component that is critical for maintaining 3‘end joining potency. Removal of the benzyl group prevents inhibitory function. Lipophylic substituents are therefore beneficial for the strand transfer inhibition, in particular the thiophenyl, furanyl and (thiophen-2-yl)phenyl substitutions. Heteroaromatic amine and amide also cause increase in 3‘ processing  inhibitory action.
When catechol-based inhibitors of IN were researched it was observed that maintaining a planar relationship with the bis-hydroxylated aryl ring increases potency. The inhibitory activity could be further optimized by including a meta-chloro substituent, enhancing the interaction of the benzyl group with the adjacent hydrophobic pocket (see figure 4: Structures A-G).
A benzyl substituted hydroxyl group (fig. 4 H) improves metal-chelating capability (compared to structure J in fig. 4) while a methoxy group (I) is much less potent due to steric clash by the additional methyl group with the catalytic metals.
When researching diketo derivates, the central pyrrole ring of structure K in fig. 4 was replaced by a series of aromatic systems having various substitution patterns. That provided optimum relative orientation of the benzyl and diketoacid (DKA) site chain. Structure L in fig. 4 resulted in 100 fold increase in potency.
Benard et al (2004) synthesized INIs with a quinoline subunit and an ancillary aromatic ring linked by functionalized spacers such as amide, hydrazide, urea and hydroxyprop-1-en-3-one moiety. They found that the amide group containing derivatives were the most promising ones. By synthesizing series of styrylquinones researchers found out that a carboxyl group at C-7, a hydroxylgroup at C-8 in the quinoline subunit and an ancillary phenyl ring (Figure 4: Structure M) are required for inhibition, although alterations of the ring are tolerated. Two hydroxyl groups on the ancillary phenyl ring are also required for inhibitory potency.