Toward rational fragment-based lead design without 3D structures.
Fragment-based lead discovery (FBLD) has become a prime component of the armamentarium of modern drug design programs. FBLD identifies low molecular weight ligands that weakly bind to important biological targets. Three-dimensional structural information about the binding mode is provided by X-ray crystallography or NMR spectroscopy and is subsequently used to improve the lead compounds. Despite tremendous success rates, FBLD relies on the availability of high-resolution structural information, still a bottleneck in drug discovery programs. To overcome these limitations, we recently demonstrated that the meta-structure approach provides an alternative route to rational lead identification in cases where no 3D structure information about the biological target is available. Combined with information-rich NMR data, this strategy provides valuable information for lead development programs. We demonstrate with several examples the feasibility of the combined NMR and meta-structure approach to devise a rational strategy for fragment evolution without resorting to highly resolved protein complex structures.
Department of Structural and Computational Biology, Max F. Perutz Laboratories,  University of Vienna , Vienna Biocenter Campus 5, A-1030 Vienna, Austria.
Morkos A
MA
Henen
Nicolas
N
Coudevylle
Leonhard
L
Geist
Robert
R
Konrat
D018360:Crystallography, X-Ray; D015195:Drug Design; D055808:Drug Discovery; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D051176:beta Catenin / Q000737:chemistry
D051176:beta Catenin