A practical method for targeted library design balancing lead-like properties with diversity.
A practical and pragmatic method is demonstrated that aligns lead-like properties with compound diversity for the picking of compounds to synthesise from large virtual libraries. Methods are highlighted for decreasing synthetic attrition through the prior filtration of reagents sets grouped by reaction type. Also disclosed are protocols that use a combination of predicted physicochemical parameters and potential toxicological liabilities to enable the synthesis of lead-like compounds with a low potential risk of exhibiting toxicity or undesirable physicochemical properties. Lastly, a compound-picking process for a 2D compound matrix is demonstrated that maximises the diversity coverage whilst minimising synthetic effort. Thus a very highly optimised process is shown that delivers premium sample quality where lead-likeness and novelty are aligned to afford the best possible enhancement for the corporate compound collection.
Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leics, LE11 5RH, UK. mike.stocks@astrazeneca.com
Michael J
MJ
Stocks
Gareth R H
GR
Wilden
Garry
G
Pairaudeau
Matthew W D
MW
Perry
John
J
Steele
Jeffrey P
JP
Stonehouse
D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry; D054852:Small Molecule Libraries
D001384:Azetidines; D006571:Heterocyclic Compounds; D054852:Small Molecule Libraries; C082735:azetidine