Descriptor-free molecular discovery in large libraries by adaptive substituent reordering.
Molecular discovery often involves identification of the best functional groups (substituents) on a scaffold. When multiple substitution sites are present, the number of possible substituent combinations can be very large. This article introduces a strategy for efficiently optimizing the substituent combinations by iterative rounds of compound sampling, substituent reordering to produce the most regular property landscape, and property estimation over the landscape. Application of this approach to a large pharmaceutical compound library demonstrates its ability to find active compounds with a threefold reduction in synthetic and assaying effort, even without knowing the molecular identity of any compound.
Department of Chemical Engineering, Princeton University, Princeton, NJ 08544, USA.
Scott R
SR
McAllister
Xiao-Jiang
XJ
Feng
Peter A
PA
DiMaggio
Christodoulos A
CA
Floudas
Joshua D
JD
Rabinowitz
Herschel
H
Rabitz
D000465:Algorithms; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004364:Pharmaceutical Preparations; D021281:Quantitative Structure-Activity Relationship
D004364:Pharmaceutical Preparations