A Practical Method for Targeted Library Design Balancing Lead-like Properties with Diversity

Abstract Choosing the right compounds to synthesise from large virtual combinatorial libraries is a current challenge for the pharmaceutical industry. Herein we describe a highly optimised method that aligns lead‐like properties with compound diversity. The methods are illustrated by considering a two‐dimensional library based on the interesting spirocyclic bis ‐azetidine template. magnified image 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.