Spectrometric and computational studies of the binding of HIV-1 integrase inhibitors to viral DNA extremities
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 targe...
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| Format: | Article |
| Language: | English |
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PeerJ Inc.
2019-12-01
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| Series: | PeerJ Physical Chemistry |
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| Online Access: | https://peerj.com/articles/pchem-6.pdf |
| _version_ | 1828444326056689664 |
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| author | Léa El Khoury Krystel El Hage Jean-Philip Piquemal Serge Fermandjian Richard G. Maroun Nohad Gresh Zeina Hobaika |
| author_facet | Léa El Khoury Krystel El Hage Jean-Philip Piquemal Serge Fermandjian Richard G. Maroun Nohad Gresh Zeina Hobaika |
| author_sort | Léa El Khoury |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T21:42:46Z |
| format | Article |
| id | doaj.art-5f06c5a16c3c4158b12d768262ace22d |
| institution | Directory Open Access Journal |
| issn | 2689-7733 |
| language | English |
| last_indexed | 2024-12-10T21:42:46Z |
| publishDate | 2019-12-01 |
| publisher | PeerJ Inc. |
| record_format | Article |
| series | PeerJ Physical Chemistry |
| spelling | doaj.art-5f06c5a16c3c4158b12d768262ace22d2022-12-22T01:32:28ZengPeerJ Inc.PeerJ Physical Chemistry2689-77332019-12-011e610.7717/peerj-pchem.6Spectrometric and computational studies of the binding of HIV-1 integrase inhibitors to viral DNA extremitiesLéa El Khoury0Krystel El Hage1Jean-Philip Piquemal2Serge Fermandjian3Richard G. Maroun4Nohad Gresh5Zeina Hobaika6Laboratoire de Chimie Théorique, UMR7616 CNRS, Sorbonne Université, Paris, FranceChemistry and Biology Nucleo(s)tides and Immunology for Therapy (CBNIT), UMR 8601 CNRS, UFR Biomedicale, Paris, FranceUR EGP, Centre d’Analyses et de Recherche, Faculté des Sciences, Université Saint-Joseph de Beyrouth, Beirut, LebanonChemistry and Biology Nucleo(s)tides and Immunology for Therapy (CBNIT), UMR 8601 CNRS, UFR Biomedicale, Paris, FranceUR EGP, Centre d’Analyses et de Recherche, Faculté des Sciences, Université Saint-Joseph de Beyrouth, Beirut, LebanonLaboratoire de Chimie Théorique, UMR7616 CNRS, Sorbonne Université, Paris, FranceUR EGP, Centre d’Analyses et de Recherche, Faculté des Sciences, Université Saint-Joseph de Beyrouth, Beirut, LebanonThree 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.https://peerj.com/articles/pchem-6.pdfHIV-1 IntegraseHalobenzene inhibitorsViral DNASpectrometric studiesComputational studies |
| spellingShingle | Léa El Khoury Krystel El Hage Jean-Philip Piquemal Serge Fermandjian Richard G. Maroun Nohad Gresh Zeina Hobaika Spectrometric and computational studies of the binding of HIV-1 integrase inhibitors to viral DNA extremities PeerJ Physical Chemistry HIV-1 Integrase Halobenzene inhibitors Viral DNA Spectrometric studies Computational studies |
| title | Spectrometric and computational studies of the binding of HIV-1 integrase inhibitors to viral DNA extremities |
| title_full | Spectrometric and computational studies of the binding of HIV-1 integrase inhibitors to viral DNA extremities |
| title_fullStr | Spectrometric and computational studies of the binding of HIV-1 integrase inhibitors to viral DNA extremities |
| title_full_unstemmed | Spectrometric and computational studies of the binding of HIV-1 integrase inhibitors to viral DNA extremities |
| title_short | Spectrometric and computational studies of the binding of HIV-1 integrase inhibitors to viral DNA extremities |
| title_sort | spectrometric and computational studies of the binding of hiv 1 integrase inhibitors to viral dna extremities |
| topic | HIV-1 Integrase Halobenzene inhibitors Viral DNA Spectrometric studies Computational studies |
| url | https://peerj.com/articles/pchem-6.pdf |
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