Computational Prospecting for the Pharmacological Mechanism of Activity: HIV-1 Inhibition by Ixoratannin A-2

Author(s): Olujide O. Olubiyi*, Thomas O. Idowu, Abiodun O. Ogundaini, Goodness Orhuah

Journal Name: Current Computer-Aided Drug Design

Volume 16 , Issue 4 , 2020


DOI : 10.2174/1573409915666190702111023

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Graphical Abstract:


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.

Keywords: Ixoratannin A-2, HIV1/AIDS, docking, molecular dynamics, ixora coccinea, CD4+.

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VOLUME: 16
ISSUE: 4
Year: 2020
Published on: 02 September, 2020
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DOI: 10.2174/1573409915666190702111023
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