In Silico Isomerization Produces Apt Negative Data for VHTS Validation

isomerization offers an attractive alternative for generating decoys for drug-like compounds that naturally mitigates many of these discrepancies. Here, we explore this proposition and prove the conjecture. We show that isomerization can produce molecules that have hydrogen bond acceptor, donor, rotatable bonds counts, charge, and surface area distributions that match experimental actives more closely than experimental decoys. While these are properties that receive a lot of attention in drug design, we also show that isomerization can effectively produce decoys that are positioned more closely to actives in property hyperspace than current experimental decoys, which tend to be highly dissimilar from the actives. The latter is a significant shortcoming that has thus far remained unreported and unaddressed. Additionally, we introduce the concept of pseudoisomers - decoys that have nearly identical atomic compositions to the actives - and show how they too can be used in VHTS validation at practically no cost. Herein, we build upon the methods, tools, and work of others to facilitate the generation of new and better validation sets more cheaply and efficiently, in the hope of moving the field of VHTS forward toward maturity. To that end, we make our code fully and freely available on GitHub (https://github.com/sivanovMU-Sofia/isomerization).