  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. 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 (delta(E)) with this
base-pair. Most compounds had DE 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 delta(SIBFA) contribution is
compared to its QC counterpart along this series of derivatives.
