Preferential binding of aryl chlorides over aryl methyl moieties in serine protease S1 pockets is well described in the literature, although the physical origins of this trend have remained unclear and continue to be a subject of discussion.  Various rationales have been proposed including differential desolvation, halogen bonding and weak hydrogen bonding effects.   In this study, we apply state-of-the-art functional group symmetry-adapted perturbation theory (F-SAPT) to show that this phenomenon may be driven principally by polar interactions distributed throughout the binding pocket, particularly arising from the amide bonds in the protein backbone.   The study demonstrates the significant potential of F-SAPT to assess the strength and nature of drug molecule - protein interactions and to help elucidate the basis of SAR of drug molecules.

Origin of preferential binding of aryl chloride groups in serine protease S1 pockets: An application of Fragment Symmetry-Adapted Perturbation Theory (F-SAPT) to drug protein binding

253rd National Meeting (2017)

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