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

Abstract

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, ∆Gs, to retroviral DNA, and that such a ranking is only governed by the binding enthalpies, ∆H, 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 ∆Etot values computed with a polarizable molecular mechanics/dynamics procedure, Sum of Interactions Between Fragments Ab initio computed (SIBFA), showed good correlations with this ∆E(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.

Quantum-Chemistry Based Design of Halobenzene Derivatives With Augmented Affinities for the HIV-1 Viral G4/C16 Base-Pair

“…E tot (SIBFA) displayed trends consistent with E (QC). This study, along with our previous ones (El Hage et al, 2014El Khoury et al, 2019) shows that it is possible to design, in a piece-wise fashion, novel derivatives targeting a well-defined, highly conserved, subset of the recognition site of a large macromolecular target. It also constitutes an essential validation step prior to large-scale polarizable molecular dynamics simulations of the complex of the entirety of the drug with the entirety of the target.…”

“…Could, thus, increases of the INSTI-INT binding affinities be attempted upon focusing on the sole "ternary" complexes of G 4 , C 16 , and a halobenzene ring? Second, recent spectrometric and computational studies of the binding of INSTIs to viral DNA extremities showed the ranking of affinities to be governed by the enthalpy ( H) component of the binding free energies ( G), the entropy component (T S) being similar for all three complexes (El Khoury et al, 2019), a "signature" for intercalative binding (Chaires, 2006). Furthermore, the H ranking of the three inhibitor affinities was itself paralleled by the corresponding ranking of the ab initio quantum chemistry (QC) intermolecular interaction energies, E(QC), of their halobenzene rings with the sole G 4 /C 16 base pair.…”

A computational overview of integrase strand transfer inhibitors (INSTIs) against emerging and evolving drug-resistant HIV-1 integrase mutants

“…A study conducted by Khoury et al ( 2019 ) showed that EVG binding to intasome has a slight preference over DTG and RAL, indicating that additional interactions of the diketo acid groups of the drugs with DNA could be essential to further enable preferential binding of DTG. EVG affects not only the residues in direct contact but also the outer-shell residues indirectly bound, particularly the double mutations, like Q148R/H and G140S/A, which has a synergetic effect on its efficacy.…”

“…The X-ray structural analysis demonstrated that in the IN–vcDNA complex, the halobenzyl ring stacks over C16 (upstream), while the C–X bond points towards the centre of the G4 (downstream) of the second strand. Therefore, a surge in the drug–vcDNA complex stability draws a parallel with an increase in drug activity and a decline in viral resistance, indicating the vitality of vcDNA end recognition for the binding affinity of INSTIs to the intasome (Khoury et al 2019 ).…”