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

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 G 4 . We have sought to increase the affinity of HR derivatives for the G 4 /C 16 base pair. We thus designed thirteen novel derivatives and computed their Quantum Chemistry (QC) intermolecular interaction energies ( E) with this base-pair. Most compounds had E 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 E(SIBFA) contribution is compared to its QC counterpart along this series of derivatives.

Development of the Quantum-Inspired SIBFA Many-Body Polarizable Force Field: Enabling Condensed-Phase Molecular Dynamics Simulations

“…This is currently in progress. This work opens a new avenue for condensed-phase simulations of complex systems as both the nonadditivity and the nonisotropy of the SIBFA potential were amply validated in numerous previous studies from our Laboratories. ,− This should ensure a safe transferability, from the training set data to proteins and nucleic acids. At this stage, it is important to note that the simple AMOEBA intramolecular potential used in this study is not optimal since its ideal bond angle was set to 108.5°.…”

Development of the Quantum Inspired SIBFA Many-Body Polarizable Force Field: Enabling Condensed Phase Molecular Dynamics Simulations

“…This work opens a new avenue for condensed phase simulations of complex systems as both the non-additivity and the non-isotropy of the SIBFA potential were amply validated in numerous previous studies from our Laboratories. 2,[76][77][78][79][80][81][82][83][84][85] This should ensure for a safe transferability, from the training set data to proteins and nucleic acids. At this stage, it is important to note that the simple AMOEBA intramolecular potential used in this study is not optimal since its ideal bond angle was set to 108.5 • .…”

Prediction of the interaction strength of an urea‐based probe toward ions in water by means of Density Functional Theory/Polarizable Continuum Model calculations

“…Overall, the computer-aided chemical probe design methodology can be deemed of interest for a very broad scientific community, from chemistry and biology up to material sciences, nanometer devices design challenges and intermolecular interaction being now pervasive in these disciplines. Most notably, this work allows for the first time to go beyond the usual DFT in vacuo approach, used to assess the strength of intermolecular interactions in most existing studies, by extrapolating results from a vacuum context to a solvated context, in the spirit of the recent study by El Darazi et al [34] comparing the affinities of several halobenzene derivatives to a targeted site of viral DNA, with DFT and polarizable molecular mechanics computations, and also performing additional PCM computations. Using a well-chosen implicit solvent model on top of a DFT model also allows to avoid an explicit solvent description and the need of long and costly dynamical simulations and force field parametrization.…”