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The HIV-1 integrase (IN) is a major target for the design of novel anti-HIVinhibitors. Among these, three inhibitors which embody a halobenzene ringderivative (HR) in their structures are presently used in clinics.High-resolution X-ray crystallography of the complexes of the IN-viral DNAtransient complex bound to each of the three inhibitors showed in all cases theHR ring to interact within a confined zone of the viral DNA. The extension ofits 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 basepair. We thus designed thirteen novel derivatives and computed their QuantumChemistry (QC) intermolecular interaction energies (delta(E)) with thisbase-pair. Most compounds had DE values significantly more favorable than thoseof the HR of the most potent halobenzene drug presently used in clinics,Dolutegravir. This should enable the improvement in a modular piece-wisefashion, the affinities of halogenated inhibitors for viral DNA (vDNA). In viewof large scale polarizable molecular dynamics simulations on the entirety ofthe IN-vDNA-inhibitor complexes, validations of the SIBFA polarizable methodare also reported, in which the evolution of each delta(SIBFA) contribution iscompared to its QC counterpart along this series of derivatives.

Quantum-Chemistry based design of halobenzene derivatives with augmented affinities for the HIV-1 viral G4/C16 base-pair