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.
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.
Laboratorium für Organische Chemie, ETH Zürich, Wolfgang-Pauli-Strasse 10, HCI, 8093, Zürich, Switzerland.
Maude
M
Giroud
Laboratorium für Organische Chemie, ETH Zürich, Wolfgang-Pauli-Strasse 10, HCI, 8093, Zürich, Switzerland.
Michael
M
Harder
Small Molecule Research, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, Building 92, 4070, Basel, Switzerland.
Bernd
B
Kuhn
Small Molecule Research, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, Building 92, 4070, Basel, Switzerland.
Wolfgang
W
Haap
Laboratorium für Organische Chemie, ETH Zürich, Wolfgang-Pauli-Strasse 10, HCI, 8093, Zürich, Switzerland.
Nils
N
Trapp
Laboratorium für Organische Chemie, ETH Zürich, Wolfgang-Pauli-Strasse 10, HCI, 8093, Zürich, Switzerland.
W Bernd
WB
Schweizer
Institut für Pharmazie und Biochemie, Johannes Gutenberg-Universität Mainz, Staudinger Weg 5, 55128, Mainz, Germany. schirmei@uni-mainz.de.
Tanja
T
Schirmeister
Laboratorium für Organische Chemie, ETH Zürich, Wolfgang-Pauli-Strasse 10, HCI, 8093, Zürich, Switzerland. diederich@org.chem.ethz.ch.
François
F
Diederich
D000577:Amides / Q000737:chemistry; D001665:Binding Sites; D056668:Cathepsin L / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D005461:Fluorine / Q000737:chemistry*; D005470:Fluorometry; D054879:Halogenation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008024:Ligands; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D011789:Quantum Theory; D014227:Triazines / Q000737:chemistry / Q000378:metabolism
D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D008024:Ligands; D014227:Triazines; D005461:Fluorine; D056668:Cathepsin L
cysteine protease inhibitors; dipolar interactions; fluorine scans; peptide bonds; quadrupolar interactions; quantum chemical calculations; π-stacking