Spectrometric and computational studies of the binding of HIV-1 integrase inhibitors to viral DNA extremities

Léa El-Khoury (1, 2) , Krystel El Hage (3) , Jean-Philip Piquemal (1) , Serge Fermandjian (3) , Richard G. Maroun (2) , Nohad Gresh (1) , Zeina Hobaika (2)

1 LCT - Laboratoire de chimie théorique
2 USJ - Université Saint-Joseph de Beyrouth
3 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques

Three integrase strand transfer inhibitors are in intensive clinical use, raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG). The onset of integrase resistance mutations limits their therapeutic efficiency. As put forth earlier, the drug affinity for the intasome could be improved by targeting preferentially the retroviral nucleobases, 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 the DTG > EVG > RAL ranking of their inhibitory activities of the intasome to correspond to that of their free energies of binding, ΔGs, to retroviral DNA, and that such a ranking is only governed by the binding enthalpies, ΔH, the entropy undergoing marginal variations. We sought whether this ranking might be reproduced through quantum chemistry (QC) Density Functional Theory calculations of intermolecular interaction energies between simplified models consisting of sole halobenzene ring and the highly conserved retroviral nucleobases G4 and C16. These calculations showed that binding of EVG has a small preference over DTG, while RAL ranked third. This indicates that additional interactions of the diketoacid parts of the drugs with DNA could be necessary to further enable preferential binding of DTG. The corresponding ΔEtot values computed with a polarizable molecular mechanics/dynamics procedure, Sum of Interactions Between Fragments Ab initio computed showed good correlations with this ΔE(QC) ranking. These validations are an important step toward the use of polarizable molecular dynamics simulations on DTG or EVG derivatives in their complexes with the complete intasome, an application now motivated and enabled by the advent of currently developed and improved massively parallel software.

Mots clés: molecular modeling; spectroscopy; integrase; HIV-1

Domaines: Chimie théorique et/ou physique

Léa El-Khoury, Krystel El Hage, Jean-Philip Piquemal, Serge Fermandjian, Richard G. Maroun, et al.. Spectrometric and computational studies of the binding of HIV-1 integrase inhibitors to viral DNA extremities. PeerJ Physical Chemistry, 2019, 1, pp.e6. ⟨10.7717/peerj-pchem.6⟩. ⟨hal-02372493⟩