Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π-Stacking of Fluorinated Phenyl Rings on Peptide Amide Bonds

Abstract

AbstractThe π‐stacking of fluorinated benzene rings on protein backbone amide groups was investigated, using a dual approach comprising enzyme–ligand binding studies complemented by high‐level quantum chemical calculations. In the experimental study, the phenyl substituent of triazine nitrile inhibitors of human cathepsin L (hCatL), which stacks onto the peptide amide bond Gly67−Gly68 at the entrance of the S3 pocket, was systematically fluorinated, and differences in inhibitory potency were measured in a fluorimetric assay. Binding affinity is influenced by lipophilicity (clog P), the dipole and quadrupole moments of the fluorinated rings, but also by additional interactions of the introduced fluorine atoms with the local environment of the pocket. Generally, the higher the degree of fluorination, the better the binding affinities. Gas phase calculations strongly support the contributions of the molecular quadrupole moments of the fluorinated phenyl rings to the π‐stacking interaction with the peptide bond. These findings provide useful guidelines for enhancing π‐stacking on protein amide fragments.

Autoren

Maude Giroud
Michael Harder
Bernd Kuhn
Wolfgang Haap
Nils Trapp
W Bernd Schweizer
Tanja Schirmeister
François Diederich

DOI

10.1002/cmdc.201600132

eISSN

1860-7187

ISSN

1860-7179

Ausgabe der Veröffentlichung

10

Zeitschrift

ChemMedChem

Sprache

en

Online publication date

2016

Paginierung

1042 - 1047

Datum der Veröffentlichung

2016

Status

Published

Herausgeber

Wiley

Herausgeber URL

http://dx.doi.org/10.1002/cmdc.201600132

Datum der Datenerfassung

2023

Titel

Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π‐Stacking of Fluorinated Phenyl Rings on Peptide Amide Bonds

Ausgabe der Zeitschrift

11

Datenquelle: Crossref

Abstract

The π-stacking of fluorinated benzene rings on protein backbone amide groups was investigated, using a dual approach comprising enzyme-ligand binding studies complemented by high-level quantum chemical calculations. In the experimental study, the phenyl substituent of triazine nitrile inhibitors of human cathepsin L (hCatL), which stacks onto the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket, was systematically fluorinated, and differences in inhibitory potency were measured in a fluorimetric assay. Binding affinity is influenced by lipophilicity (clog P), the dipole and quadrupole moments of the fluorinated rings, but also by additional interactions of the introduced fluorine atoms with the local environment of the pocket. Generally, the higher the degree of fluorination, the better the binding affinities. Gas phase calculations strongly support the contributions of the molecular quadrupole moments of the fluorinated phenyl rings to the π-stacking interaction with the peptide bond. These findings provide useful guidelines for enhancing π-stacking on protein amide fragments.

Addresses

Laboratorium für Organische Chemie, ETH Zürich, Wolfgang-Pauli-Strasse 10, HCI, 8093, Zürich, Switzerland.

Autoren

Maude Giroud
Michael Harder
Bernd Kuhn
Wolfgang Haap
Nils Trapp
W Bernd Schweizer
Tanja Schirmeister
François Diederich

DOI

10.1002/cmdc.201600132

eISSN

1860-7187

Externe Identifier

PubMed Identifier: 27095165

Funding acknowledgements

F. Hoffmann-La Roche, Basel:
ETH Research Council:

Open access

false

ISSN

1860-7179

Ausgabe der Veröffentlichung

10

Zeitschrift

ChemMedChem

Schlüsselwörter

Humans
Fluorine
Amides
Triazines
Cysteine Proteinase Inhibitors
Ligands
Fluorometry
Binding Sites
Protein Structure, Tertiary
Kinetics
Quantum Theory
Halogenation
Molecular Dynamics Simulation
Cathepsin L
Hydrophobic and Hydrophilic Interactions

Sprache

eng

Medium

Print-Electronic

Online publication date

2016

Paginierung

1042 - 1047

Datum der Veröffentlichung

2016

Status

Published

Datum der Datenerfassung

2016

Titel

Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π-Stacking of Fluorinated Phenyl Rings on Peptide Amide Bonds.

Sub types

Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

11

Datenquelle: Europe PubMed Central

Abstract

The π-stacking of fluorinated benzene rings on protein backbone amide groups was investigated, using a dual approach comprising enzyme-ligand binding studies complemented by high-level quantum chemical calculations. In the experimental study, the phenyl substituent of triazine nitrile inhibitors of human cathepsin L (hCatL), which stacks onto the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket, was systematically fluorinated, and differences in inhibitory potency were measured in a fluorimetric assay. Binding affinity is influenced by lipophilicity (clog P), the dipole and quadrupole moments of the fluorinated rings, but also by additional interactions of the introduced fluorine atoms with the local environment of the pocket. Generally, the higher the degree of fluorination, the better the binding affinities. Gas phase calculations strongly support the contributions of the molecular quadrupole moments of the fluorinated phenyl rings to the π-stacking interaction with the peptide bond. These findings provide useful guidelines for enhancing π-stacking on protein amide fragments.

Autoren

Maude Giroud
Michael Harder
Bernd Kuhn
Wolfgang Haap
Nils Trapp
W Bernd Schweizer
Tanja Schirmeister
François Diederich

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/27095165

DOI

10.1002/cmdc.201600132

eISSN

1860-7187

Ausgabe der Veröffentlichung

10

Zeitschrift

ChemMedChem

Schlüsselwörter

cysteine protease inhibitors
dipolar interactions
fluorine scans
peptide bonds
quadrupolar interactions
quantum chemical calculations
π-stacking
Amides
Binding Sites
Cathepsin L
Cysteine Proteinase Inhibitors
Fluorine
Fluorometry
Halogenation
Humans
Hydrophobic and Hydrophilic Interactions
Kinetics
Ligands
Molecular Dynamics Simulation
Protein Structure, Tertiary
Quantum Theory
Triazines

Sprache

eng

Country

Germany

Paginierung

1042 - 1047

Datum der Veröffentlichung

2016

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2017

Titel

Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π-Stacking of Fluorinated Phenyl Rings on Peptide Amide Bonds.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

11

Datenquelle: PubMed

Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π-Stacking of Fluorinated Phenyl Rings on Peptide Amide Bonds

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