Computational prospecting for pharmacological mechanism of activity: HIV-1 inhibition by Ixoratannin-A2

: Ixora coccinea a tropical ornamental shrub employed ethnomedicinal in the treatment of a number of diseases none of which include the human immunodeficiency virus (HIV) representing the infectious agent in acquired immunodeficiency syndrome. Ixoratannin A-2, one of the constituents, was identified by via virtual-screening and experimentally confirmed to possess significant anti-HIV-1 activity in an in vitro CD4+ replication assay, an activity that was observed to be reduced in degree in HIV-1 lacking Vpu. This suggests the involvement of extra-Vpu macromolecules in its antiviral activity. In the present computational search for the identity of the other macromolecules that could explain the observed activity, a panel of fourteen HIV-1 macromolecular targets was assembled against which Ixoratannin A-2 and other major phytoconstituents of I. coccinea were screened. Structural analyses of the computed ligand-bound complexes, as well as the careful investigation of the thermodynamic attributes of the predicted binding, revealed selectivity patterns that suggest multiple macromolecular involvements. While a binding interaction was found unfavourable for a number of investigated HIV/AIDS targets, a number of the targets including the multidrug resistant HIV protease enzyme, CXCR4 and the human elongin C protein were found to form sufficiently stable interaction with Ixoratannin A-2 and other natural products present in I. coccinea and which could possible explain the observed antiviral activity.