title: The Surprising Importance of Peptide Bond Contacts in Drug-Protein Interactions.
abstract: The study of noncovalent interactions, notably including drug-protein binding, relies heavily on the language of localized functional group contacts: hydrogen bonding, π-π interactions, CH-π 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.
authors.affiliation: Center for Computational Molecular Science and Technology, School of Chemistry and Biochemistry, School of Computational Science and Engineering, Georgia Institute of Technology, Atlanta, GA, 30332-0400, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Parrish
authors.affiliation: Molecular Structure and Design, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA.
authors.forename: Doree F
authors.initials: DF
authors.lastname: Sitkoff
authors.affiliation: Molecular Structure and Design, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Cheney
authors.affiliation: Center for Computational Molecular Science and Technology, School of Chemistry and Biochemistry, School of Computational Science and Engineering, Georgia Institute of Technology, Atlanta, GA, 30332-0400, USA.
authors.forename: C David
authors.identifier: http://orcid.org/0000-0002-5570-7666
authors.initials: CD
authors.lastname: Sherrill
mesh_terms: D018360:Crystallography, X-Ray; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism*; D065427:Factor Xa Inhibitors / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D008024:Ligands; D008968:Molecular Conformation; D011485:Protein Binding; D011789:Quantum Theory; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D065427:Factor Xa Inhibitors; D008024:Ligands; D015951:Factor Xa
keywords: ab initio calculations; drug design; noncovalent interactions; peptides