Abstract
The HIV-1 integrase (IN) is a major target for the design of novel anti-HIV inhibitors. Among these, three inhibitors which embody a halobenzene ring derivative (HR) in their structures are presently used in clinics. High-resolution X-ray crystallography of the complexes of the IN-viral DNA transient complex bound to each of the three inhibitors showed in all cases the HR ring to interact within a confined zone of the viral DNA, limited to the highly conserved 5′CpA 3′/5′TpG 3′ step. The extension of its extracyclic CX bond is electron-depleted, owing to the existence of the “sigma-hole.” It interacts favorably with the electron-rich rings of base G4. We have sought to increase the affinity of HR derivatives for the G4/C16 base pair. We thus designed thirteen novel derivatives and computed their Quantum Chemistry (QC) intermolecular interaction energies (ΔE) with this base-pair. Most compounds had ΔE values significantly more favorable than those of the HR of the most potent halobenzene drug presently used in clinics, Dolutegravir. This should enable the improvement in a modular piece-wise fashion, the affinities of halogenated inhibitors for viral DNA (vDNA). In view of large scale polarizable molecular dynamics simulations on the entirety of the IN-vDNA-inhibitor complexes, validations of the SIBFA polarizable method are also reported, in which the evolution of each ΔE(SIBFA) contribution is compared to its QC counterpart along this series of derivatives.
Highlights
The HIV-1 integrase (IN) catalyzes the transfer of a viral DNA strand into the genome of the host cell (Lesbats et al, 2016)
Three integrase inhibitors have been approved by the FDA in anti-HIV therapies, Raltegravir (RAL) (Summa et al, 2008), Elvitegravir (EVG) (Shimura et al, 2008), and Dolutegravir (DTG) (Underwood et al, 2012)
We did not allow for conformational relaxation around the glycosidic bonds of G4 and C16 since we considered that this viral DNA base pair is held in an experimental position “tailored” for DTG: any additional positional relaxation in complexes with derivatives with bulkier ligands could a priori be expected to further optimize, rather than penalize, the binding of such derivatives, with possibly an even more favorable outcome than the one from the present study
Summary
The HIV-1 integrase (IN) catalyzes the transfer of a viral DNA (vDNA) strand into the genome of the host cell (Lesbats et al, 2016). It is involved in reverse transcription (Hironori et al, 2009), nuclear import (Mouscadet et al, 2007), and HIV-1 particle maturation (Kessl et al, 2016). It has no counterpart in human cells and constitutes an emerging target for the design of novel anti-retroviral inhibitors (Liao et al, 2010).
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