A validation study on the practical use of automated de novo design.
The de novo design program Skelgen has been used to design inhibitor structures for four targets of pharmaceutical interest. The designed structures are compared to modeled binding modes of known inhibitors (i) visually and (ii) by means of a novel similarity measure considering the size and spatial proximity of the maximum common substructure of two small molecules. It is shown that the Skelgen algorithm generates representatives of many inhibitor classes within a very short time and that the new similarity measure is useful for comparing and clustering designed structures. The results demonstrate the necessity of properly defining search constraints in practical applications of de novo design.
Stahl
Martin
M
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Todorov
Nikolay P
NP
James
Tim
T
Mauser
Harald
H
Boehm
Hans-Joachim
HJ
Dean
Philip M
PM
D000465:Algorithms; D001331:Automation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008958:Models, Molecular
D004791:Enzyme Inhibitors