Bioactivity-guided mapping and navigation of chemical space.
The structure- and chemistry-based hierarchical organization of library scaffolds in tree-like arrangements provides a valid, intuitive means to map and navigate chemical space. We demonstrate that scaffold trees built using bioactivity as the key selection criterion for structural simplification during tree construction allow efficient and intuitive mapping, visualization and navigation of the chemical space defined by a given library, which in turn allows correlation of this chemical space with the investigated bioactivity and further compound design. Brachiation along the branches of such trees from structurally complex to simple scaffolds with retained yet varying bioactivity is feasible at high frequency for the five major pharmaceutically relevant target classes and allows for the identification of new inhibitor types for a given target. We provide proof of principle by identifying new active scaffolds for 5-lipoxygenase and the estrogen receptor ERalpha.
Renner
Steffen
S
Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Dortmund, Germany.
van Otterlo
Willem A L
WA
Dominguez Seoane
Marta
M
Möcklinghoff
Sabine
S
Hofmann
Bettina
B
Wetzel
Stefan
S
Schuffenhauer
Ansgar
A
Ertl
Peter
P
Oprea
Tudor I
TI
Steinhilber
Dieter
D
Brunsveld
Luc
L
Rauh
Daniel
D
Waldmann
Herbert
H
D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003198:Computer Simulation; D016208:Databases, Factual; D047628:Estrogen Receptor alpha / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D012984:Software; D013329:Structure-Activity Relationship
D047628:Estrogen Receptor alpha; D054852:Small Molecule Libraries; D001094:Arachidonate 5-Lipoxygenase