High-Level Quantum Chemistry Empowers the Wrapping Technology for Drug Design
This chapter introduces an analysis based on high-level quantum mechanics, specifically incorporating electron correlation effects, to enrich and further empower the paradigmatic concept of “dehydron-wrapping drug.” This type of analysis provides the required guidance for the incorporation of halogens as wrapping groups in the drug chemical scaffold. The chapter explores the possibility that the group that wraps exogenously a dehydron upon drug binding may also effectively interact through quantum mechanical forces with the carbonyl oxygen paired by the preformed dehydron in the target protein. This type of interaction involves dispersion forces that induce an anisotropic electron distribution on the halogen orbital called a “sigma hole.” This electron anisotropy promotes the formation of a halogen bond with the carbonyl oxygen in the target protein. Thus, the intermolecular halogen bond is now coupled to the wrapping interaction, and the wrapping group is now a halogen with significant polarizability (Cl, Br, I), capable of eliciting significant dispersion force. This novel modality of ligand association involves two coupled drug–target interactions branching from the same drug substituent. The quantum mechanical analysis advocating the inclusion of halogens as wrappers is likely to significantly empower drug design as it reinforces the dehydronic drag on the drug through favorable electron correlation effects.
KeywordsCarbonyl Oxygen Dispersion Force Halogen Bond Backbone Carbonyl Electron Correlation Effect