Spectrometric and computational studies of the binding of HIV-1 integrase inhibitors to viral DNA extremities
- Published
- Accepted
- Subject Areas
- Theoretical and Computational Chemistry, Biophysical Chemistry, Physical Chemistry (other)
- Keywords
- HIV-1 Integrase, halobenzene inhibitors, Viral DNA, Spectrometric studies, Computational studies
- Copyright
- © 2019 El Khoury et al.
- Licence
- This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ Preprints) and either DOI or URL of the article must be cited.
- Cite this article
- 2019. Spectrometric and computational studies of the binding of HIV-1 integrase inhibitors to viral DNA extremities. PeerJ Preprints 7:e27833v1 https://doi.org/10.7287/peerj.preprints.27833v1
Abstract
Three Integrase (IN) strand transfer inhibitors are in intensive clinical use, raltegravir, elvitegravir anddolutegravir. However, the onset of IN resistance mutations limits their therapeutic efficiency. As put forth earlier, the drug affinity for the intasome could be improved by targeting preferentially the retroviralnucleobases, which are little, if at all, mutation-prone. We report experimental results of anisotropy fluorescence titrations of viral DNA by these three drugs . These show that the ranking of their inhibitory activities of the intasome corresponds to that of their free energies of binding, D Gs,to retroviral DNA, and that such a ranking is only governed by the binding enthalpies, D H, the entropy undergoing marginal variations.This ranking can therefore be directly correlated to that of model Quantum Chemistry (QC) calculations of intermolecular interaction energies of the sole halobenzene ring with the highly conserved retroviral nucleobases G4 and C14, using Density Functional Theory. This DE(QC) ranking is in turn reproduced by the corresponding DE tot values computed with a polarizable molecular mechanics/dynamics procedure, SIBFA (Sum of Interactions Between Fragments Ab initio computed). Such validations should enable polarizable molecular dynamics simulations on more potent inhibitors in their complexes with the complete intasome. Such derivatives should principally encompass modified halobenzene rings.
Author Comment
This is a submission to PeerJ Physical Chemistry for review.