A fragment bound its protein target - author O. Cala ISA UMR 5280

Our research spans the field of Chemical Biology, Structural Biology and Drug Discovery and mainly focuses on the development of new molecules to fight cancer, inflammation, as well as infectious diseases through the development of novel antibiotics and antiviral compounds. Our approach is based on the combination of NMR spectroscopy and fragment library screening. We also develop strategies for the design of protein-protein interaction inhibitors, which represent a very challenging class of drugs.
We develop a fragment library (organic compounds with molecular weight <250 Da) that consists of more than 700 fragments. The scope of chemical space covered by this small set of fragment molecules is equivalent to the scope presented by a large classical HTS library of 240 000 compounds (>400 Da).
We develop NMR-based analytical approaches for the structural investigation of complexes between proteins and weak affinity ligands (µM-mM). We especially address the question of the binding specificity, binding site, and binding mode of fragments or larger molecules, using both ligand-observed NMR experiments (WaterLOGSY, STD, Transferred-NOESY experiments) and protein-observed NMR experiments (HSQC, HMQC-type experiments).

Recent highlights

  • Development of a program CSPsim dedicated to the fast determination of 3D structures for protein-fragment complexes (project PLUS funded by the National Research Agency ANRJCJC2011-2014). The program uses experimental and back-calculated chemical shift perturbations observed on protein NMR spectra to filter ligand positions obtained by a docking program.
  • Modification of the docking program PLANTS for the guided-docking of protein-ligand complexes using chemical shift perturbations.
  • Valorisation of the ANR-PLUS project with SATT PULSALYS to develop a program suitable for pharmaceutical companies.

Contact: Isabelle KRIMM, CNRS researcher – Group leader – isabelle.krimm@isa-lyon.fr