Jean-Paul Renaud, Cédric Atmanene, Gilbert Bey, Fabrice Ciesielski, Gautier Desmyttere, Vincent Desserich, Cyrille Grandjean, Valéry Laurent, Pascal Muller, Dominique Roecklin, Céline Ronin, Gilles Schneider, Muriel Uhring and Valérie Vivat

Chief Scientific Officer, Science &Technology, NovAliX, Boulevard Sébastien Brant, BP 30170, F-67405 Illkirch, France

Abstract:

Noncovalent mass spectrometry is emerging as a powerful tool providing complementary information to other biophysical techniques that can be used at different stages of early-stage drug discovery [1, 2]: (i) for the thorough assessment of protein quality; (ii) as an efficient secondary screening to remove false positives from a primary high-throughput screening or a virtual screening by assessing the physical binding of the primary hits to the target, (iii) as a fast primary screening using focussed or fragment libraries, and (iv) as a high-information-content technique for the detailed characterization of ligand-target interaction in terms of stoichiometry, covalent character, specificity, and affinity.

Hit validation by noncovalent mass spectrometry proves to be very efficient at increasing the success rate inobserving the presence of the ligand in the crystal structure. Furthermore, collision-induced dissociation experiments can serve to evaluate the enthalpic part of the binding energy and are thus useful in guiding the hit-to-lead process. This label-free technique consumes very low protein amounts, has been automated, and its sensitivity makes it suitable for fragment-based drug discovery [3].

The use of non-covalent mass spectrometry will be illustrated by several examples ranging from routine quality control of proteins to automated ligand screening, SBDD and FBDD.

References:

[1]  Vivat et al. (2010) “Native MS: an ‘ESI’ way to support structure- and fragment-based drug discovery” Future Med. Chem. 1: 35-50.
[2]  Renaud and Delsuc (2009) “Biophysical techniques for ligand screening and drug design” Curr. Opin. Pharmacol. 9: 622-628. [3]        Hoffer et al. (2011) “Fragment-based drug design: computational and experimental state of the art” Comb. Chem. High Throughput Screen. 14: 500-520.