Title:Computational Prospecting for the Pharmacological Mechanism of Activity: HIV-1 Inhibition by Ixoratannin A-2
VOLUME: 16 ISSUE: 4
Author(s):Olujide O. Olubiyi*, Thomas O. Idowu, Abiodun O. Ogundaini and Goodness Orhuah
Affiliation:Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife
Keywords:Ixoratannin A-2, HIV1/AIDS, docking, molecular dynamics, ixora coccinea, CD4+.
Abstract:
Background: Ixora coccinea is a tropical ornamental shrub employed in ethnomedicine for the
treatment of a number of diseases none of which include the Human Immunodeficiency Virus (HIV) infection.
Ixoratannin A-2, one of the constituents, was previously identified via virtual-screening and experimentally
confirmed to possess significant anti-HIV-1 activity in an in vitro CD4+ replication assay. This
activity was observed to be significantly reduced in degree in viruses lacking the protein Vpu. This suggests
the involvement of Vpu as well as other extra-Vpu macromolecules in its antiviral activity.
Methods: In the present computational search for the identity of the other macromolecules that could possibly
explain the observed activity, a panel of fourteen established HIV-1 macromolecular targets was assembled
against which ixoratannin A-2 and other major phytoconstituents of I. coccinea were virtually
screened.
Results: Structural analyses of the computed ligand-bound complexes, as well as the careful investigation
of the thermodynamic attributes of the predicted binding, revealed subtle selectivity patterns at the atomistic
level that suggest the likely involvement of multiple macromolecular processes. Some of the binding interactions
were found to be thermodynamically favourable, including the multidrug-resistant HIV protease
enzyme, CXCR4 and the human elongin C protein all of which formed reasonably strong interactions with
ixoratannin A-2 and other constituents of I. coccinea.
Conclusion: Ixoratannin A-2’s ability to favourably interact with multiple HIV-1 and human targets could
explain its observed extra-Vpu antiviral activity. This, however, does not imply uncontrolled binding with
all available targets; on the other hand, molecular size of ixoratannin A-2 and combination of functional
groups confer on it a decent level of selectivity against many of the investigated HIV/AIDS targets.
