Intern
  • Superposition of Cathepsin K and other proteases (Image: Natalia Yuan Chen)
  • Structure of AAA+ ATPase p97 (PDB 5C1B) (Image: Natalia Yuan Chen)
The Sotriffer Group: Computational Medicinal Chemistry

Drug Design

Fragment-based drug discovery

fragment-based drug design (Images: Sebastian Bothe; Dissertation, 2021)
(Images: Sebastian Bothe; Dissertation, 2021)

 

Fragment‐based approaches aim to identify the smallest molecules capable of binding to a given target. While the chemical space can thereby be searched more efficiently, it comes with the experimental and computational challenge that detect rather weak binding events need to be detected. We apply biophysical techniques (BLI, NMR, X-ray) for experimental fragment screening and investigate how computational methods are most fruitfully applied in for fragment-based drug design.

Publications on this topic:

C. Herbst, S. Endres, R. Würz, C. Sotriffer
Assessment of fragment docking and scoring with the endothiapepsin model system
Arch. Pharm. 2024, 357, e2400061

M. Zehe, J. Kehrein, C. Schollmayer, C. Plank, H. Kovacs, E. Merino Asumendi, U. Holzgrabe, C. Grimm, C. Sotriffer
Combined in-solution fragment screening and crystallographic binding-mode analysis with a two-domain Hsp70 construct
ACS Chem. Biol. 2024, 19, 392–406

S. Bothe, P. Hänzelmann, S. Böhler, J. Kehrein, M. Zehe, C. Wiedemann, U. A. Hellmich, R. Brenk, H. Schindelin, C. Sotriffer
Fragment screening using biolayer interferometry reveals ligands targeting the SHP-motif binding site of the AAA+ ATPase p97
Commun. Chem. 2022, 5, 169

Covalent ligands

covalent inhibitors
 

 

The design of targeted covalent inhibitors, i.e., ligands that bind covalently to a specific target, must consider their noncovalent interactions as well as the covalent reaction with the protein. This requires a combination of classical force-field-based methods and quantum mechanical calculations. One of the targets for which we are developing covalent inhibitors is the chlamydial deubiquitinase  ChlaDUB1.

Publications on this topic:

T. Zimmermann, E. Endres, C. Sotriffer, M. Decker
Correlating predicted reactivities with experimental inhibition data of covalent ChlaDUB1 inhibitors
ACS Med. Chem. Lett. 2024, 15, 1708-1714

E. Endres, N. Yuan Chen, C. Sotriffer
MD-based assessment of covalent inhibitors in noncovalent association complexes: Learning from cathepsin K as a test case
J. Chem. Inf. Model. 2023, 63, 3186-3197

C. Sotriffer
Docking of covalent ligands: challenges and approaches
Molecular Informatics 2018, 37, 1800062