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.
McAllister
Scott R
SR
Department of Chemical Engineering, Princeton University, Princeton, NJ 08544, USA.
Feng
Xiao-Jiang
XJ
DiMaggio
Peter A
PA
Floudas
Christodoulos A
CA
Rabinowitz
Joshua D
JD
Rabitz
Herschel
H
D000465:Algorithms; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004364:Pharmaceutical Preparations; D021281:Quantitative Structure-Activity Relationship
D004364:Pharmaceutical Preparations