High-Level Quantum Chemistry Empowers the Wrapping Technology for Drug Design

  • Ariel Fernández Stigliano


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.


Carbonyl Oxygen Dispersion Force Halogen Bond Backbone Carbonyl Electron Correlation Effect 
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  1. 1.
    Wilcken R, Markus O, Zimmermann MO, Andreas Lange A, Andreas C, Joerger AC, Frank M, Boeckler FM (2013) Principles and applications of halogen bonding in medicinal chemistry and chemical biology. J Med Chem 56:1363–1388CrossRefPubMedGoogle Scholar
  2. 2.
    Wang J, Wang W, Kollman PA, Case DA (2006) Automatic atom type and bond type perception in molecular mechanical calculations. J Mol Gr Model 25:247–260CrossRefGoogle Scholar
  3. 3.
    Lu YX, Zou JW, Fan JC, Zhao WN, Jiang YJ, Yu QS (2009) Ab initio calculations on halogen-bonded complexes and comparison with density functional methods. J Comput Chem 30:725–732CrossRefPubMedGoogle Scholar
  4. 4.
    Kuhn B, Fuchs JE, Reutlinger M, Stahl M, Taylor NR (2011) Rationalizing tight ligand binding through cooperative interaction networks. J Chem Inf Model 51:3180–3198CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.National Research Council–CONICETBuenos AiresArgentina
  2. 2.Former Karl F. Hasselmann Endowed Chair Professor of BioengineeringRice UniversityHoustonUSA

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