Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 23, Issue 33, Pages 7887-7890Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201701031
Keywords
ab initio calculations; drug design; noncovalent interactions; peptides
Categories
Funding
- US DOE Computational Science Graduate Fellowship [DE-FG02- 97ER25308]
- US National Science Foundation [CHE-1566192]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1566192] Funding Source: National Science Foundation
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The study of noncovalent interactions, notably including drug-protein binding, relies heavily on the language of localized functional group contacts: hydrogen bonding, pi-pi interactions, CH-pi contacts, halogen bonding, etc. Applying the state-of-the-art functional group symmetry-adapted perturbation theory (F-SAPT) to an important question of chloro versus methyl aryl substitution in factor Xa inhibitor drugs, we find that a localized contact model provides an incorrect picture for the origin of the enhancement of chloro-containing ligands. Instead, the enhancement is found to originate from many intermediate-range contacts distributed throughout the binding pocket, particularly including the peptide bonds in the protein backbone. The contributions from these contacts are primarily electrostatic in nature, but require ab initio computations involving nearly the full drug-protein pocket system to be accurately quantified.
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