Spectrometric and computational studies of the binding of HIV-1 integrase inhibitors to viral DNA extremities
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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.
Cite this as
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 PeerJ Preprints 7:e27833v1 https://doi.org/10.7287/peerj.preprints.27833v1note This preprint is not peer-reviewed. You may wish to reference the subsequent peer-reviewed version of this article.
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This is a submission to PeerJ Physical Chemistry for review.
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Competing Interests
The authors declare that they have no competing interests.
Author Contributions
Lea El Khoury conceived and designed the experiments, performed the experiments, analyzed the data, contributed reagents/materials/analysis tools, prepared figures and/or tables, performed the computation work, authored or reviewed drafts of the paper.
Krystel El Hage performed the experiments, prepared figures and/or tables, performed the computation work.
Jean-Philip Piquemal analyzed the data, performed the computation work, authored or reviewed drafts of the paper, approved the final draft.
Serge Fermandjian conceived and designed the experiments, analyzed the data, authored or reviewed drafts of the paper, approved the final draft.
Richard Maroun conceived and designed the experiments, analyzed the data, authored or reviewed drafts of the paper, approved the final draft.
Nohad Gresh analyzed the data, prepared figures and/or tables, performed the computation work, authored or reviewed drafts of the paper, approved the final draft.
Zeina Hobaika conceived and designed the experiments, analyzed the data, contributed reagents/materials/analysis tools, prepared figures and/or tables, authored or reviewed drafts of the paper, approved the final draft.
Data Deposition
The following information was supplied regarding data availability:
Nine raw data base data have been supplied, denoted as LTR32*.xls, along with a file "Ras Data Collection.docx" specifying their content.
Funding
This was supported by the Grand Equipement National de Calcul Intensif (GENCI): Institut du Développement et des Ressources en Informatique Scientifique (IDRIS), Centre Informatique de l′Enseignement Supérieur (CINES), France, project No. x2009-075009), and the Centre de Ressources Informatiques de Haute Normandie (CRIHAN, Rouen, France), project 1998053. This was funded by the Research Council of Saint- Joseph University of Beirut, Lebanon (Project FS71), the Lebanese National Council for Scientific Research, CNRS-L (Project FS80), as well as the French Institute- Lebanon and the French-Lebanese Program CEDRE (Project 35327UJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
