skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: The Surprising Importance of Peptide Bond Contacts in Drug–Protein Interactions

Journal Article · · Chemistry - A European Journal
 [1];  [2];  [2]; ORCiD logo [1]
  1. Georgia Inst. of Technology, Atlanta, GA (United States)
  2. Bristol-Myers Squibb Company, Pennington, NJ (United States)
+ Show Author Affiliations

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.

Research Organization:
Krell Institute, Ames, IA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
FG02-97ER25308
OSTI ID:
1533136
Alternate ID(s):
OSTI ID: 1373973
Journal Information:
Chemistry - A European Journal, Vol. 23, Issue 33; ISSN 0947-6539
Publisher:
ChemPubSoc EuropeCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 24 works
Citation information provided by
Web of Science

References (24)

Contemporary developments in the discovery of selective factor Xa inhibitors: A review journal October 2016
Efficient Drug Lead Discovery and Optimization journal June 2009
Structure-based Drug Design of Pyrrolidine-1, 2-dicarboxamides as a Novel Series of Orally Bioavailable Factor Xa Inhibitors journal June 2007
Discovery of the Novel Antithrombotic Agent 5-Chloro- N -({(5 S )-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939):  An Oral, Direct Factor Xa Inhibitor journal September 2005
Calculation of Protein-Ligand Binding Affinities journal June 2007
Spatial assignment of symmetry adapted perturbation theory interaction energy components: The atomic SAPT partition journal July 2014
Evidence for CCl/CBr⋅⋅⋅π Interactions as an Important Contribution to Protein-Ligand Binding Affinity journal March 2009
Levels of symmetry adapted perturbation theory (SAPT). I. Efficiency and performance for interaction energies journal March 2014
Evidence for CCl/CBr⋅⋅⋅π Interactions as an Important Contribution to Protein-Ligand Binding Affinity journal March 2009
Symmetry-adapted perturbation theory of intermolecular forces: Symmetry-adapted perturbation theory journal August 2011
Factor Xa Inhibitors:  S1 Binding Interactions of a Series of N -{( 3S )-1-[( 1S )-1-Methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides † journal April 2007
Fully ab initio protein-ligand interaction energies with dispersion corrected density functional theory journal May 2012
Dispersion dominated halogen–π interactions: energies and locations of minima journal January 2010
λ-Dynamics free energy simulation methods journal August 2009
A Semiempirical Quantum Mechanical Solvation Model for Solvation Free Energies in All Alkane Solvents journal May 1995
Perturbation Theory Approach to Intermolecular Potential Energy Surfaces of van der Waals Complexes journal November 1994
Density fitting and Cholesky decomposition approximations in symmetry-adapted perturbation theory: Implementation and application to probe the nature of π-π interactions in linear acenes journal May 2010
Factor Xa Inhibitors: Next-Generation Antithrombotic Agents journal September 2010
Molecular Recognition at the Active Site of Factor Xa: Cation-π Interactions, Stacking on Planar Peptide Surfaces, and Replacement of Structural Water journal December 2011
Limits of Free Energy Computation for Protein−Ligand Interactions journal April 2010
Computations of Standard Binding Free Energies with Molecular Dynamics Simulations journal February 2009
Large-scale symmetry-adapted perturbation theory computations via density fitting and Laplace transformation techniques: Investigating the fundamental forces of DNA-intercalator interactions journal November 2011
Chemical Assignment of Symmetry-Adapted Perturbation Theory Interaction Energy Components: The Functional-Group SAPT Partition journal September 2014
Design, Structure−Activity Relationships, X-ray Crystal Structure, and Energetic Contributions of a Critical P1 Pharmacophore: 3-Chloroindole-7-yl-Based Factor Xa Inhibitors ⊥ ‡ journal December 2008

Cited By (4)

Stacking Interactions of Heterocyclic Drug Fragments with Protein Amide Backbones journal March 2018
Recent developments in symmetry‐adapted perturbation theory journal November 2019
On the applicability of functional-group symmetry-adapted perturbation theory and other partitioning models for chiral recognition – the case of popular drug molecules interacting with chiral phases journal January 2019
Self-consistent charge embedding at very low cost, with application to symmetry-adapted perturbation theory journal July 2019

Similar Records

Supramolecular Assembly of Peptide Amphiphiles
Journal Article · Wed Sep 06 00:00:00 EDT 2017 · Accounts of Chemical Research · OSTI ID:1533136
+1 more
Structure and Functional Properties of the Active Form of the Proteolytic Complex, ClpP1P2, from Mycobacterium tuberculosis
Journal Article · Mon Feb 08 00:00:00 EST 2016 · Journal of Biological Chemistry · OSTI ID:1533136
+4 more
Structure of a C-terminal AHNAK peptide in a 1:2:2 complex with S100A10 and an acetylated N-terminal peptide of annexin A2
Journal Article · Tue Jan 01 00:00:00 EST 2013 · Acta Crystallographica. Section D: Biological Crystallography · OSTI ID:1533136

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Chemistry
ab initio calculations
drug design
noncovalent interactions
peptides