The effect of Geometrical Isomerism of 3,5-dicaffeoylquinic acid on its binding affinity to HIV-integrase enzyme: a molecular docking study

Abstract

A potent plant-derived HIV-1 inhibitor, 3,5-dicaffeoylquinic acid (diCQA), has been shown to undergo isomerisation upon UV exposure where the naturally occurring 3𝑡𝑟𝑎𝑛𝑠,5𝑡𝑟𝑎𝑛𝑠-diCQA isomer gives rise to the 3𝑐𝑖𝑠,5𝑡𝑟𝑎𝑛𝑠-diCQA, 3𝑡𝑟𝑎𝑛𝑠,5𝑐𝑖𝑠-diCQA, and 3𝑐𝑖𝑠,5𝑐𝑖𝑠- diCQA isomers. In this study, inhibition of HIV-1 INT by UV-induced isomers was investigated usingmolecular dockingmethods. Here, density functional theory (DFT) models were used for geometry optimization of the 3,5-diCQA isomers. The YASARA and Autodock VINA software packages were then used to determine the binding interactions between the HIV-1 INT catalytic domain and the 3,5-diCQA isomers and the Discovery Studio suite was used to visualise the interactions between the isomers and the protein. The geometrical isomers of 3,5-diCQA were all found to bind to the catalytic core domain of the INT enzyme. Moreover, the 𝑐𝑖𝑠 geometrical isomers were found to interact with the metal cofactor of HIV-1INT, a phenomenon which has been linked to antiviral potency. Furthermore, the 3𝑡𝑟𝑎𝑛𝑠,5𝑐𝑖𝑠-diCQA isomer was also found to interact with both LYS156 and LYS159 which are important residues for viral DNA integration. The differences in binding modes of these naturally coexisting isomers may allow wider synergistic activity which may be beneficial in comparison to the activities of each individual isomer.