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In Silico Isomerization Produces Apt Negative Data for VHTS Validation
Stefan M Ivanov1,2,3
1Faculty of Pharmacy, Medical University of Sofia, Dunav 2 Str., Sofia 1000, Bulgaria.
Journal of Chemical Information and Modeling
|July 23, 2026
Summary
In silico isomerization offers a cost-effective method for generating better decoys for virtual high-throughput screening (VHTS) validation sets, improving drug discovery efficiency.
Area of Science:
- Computational Chemistry
- Drug Discovery
- Cheminformatics
Background:
- Virtual high-throughput screening (VHTS) relies on robust validation sets with decoys closely matching active compounds.
- Current methods for creating these validation sets are iterative, expensive, and can introduce discrepancies between actives and decoys.
- Previous research suggested *in silico* isomerization as a potential solution to mitigate these discrepancies.
Purpose of the Study:
- To explore and validate the conjecture that *in silico* isomerization can generate superior decoys for VHTS.
- To demonstrate that isomeric decoys better match experimental actives in key physicochemical properties and property space.
- To introduce pseudoisomers as a novel, cost-effective decoy generation strategy.
Main Methods:
- Utilized *in silico* isomerization to generate decoys for drug-like compounds.
- Compared physicochemical properties (hydrogen bond acceptors/donors, rotatable bonds, charge, surface area) of isomeric decoys against experimental decoys and actives.
- Analyzed the positioning of decoys within property hyperspace relative to actives.
- Introduced and evaluated pseudoisomers as near-identical atomic composition decoys.
Main Results:
- Isomerization successfully produced decoys with property distributions closely matching experimental actives, outperforming experimental decoys.
- Isomeric decoys were found to be positioned closer to actives in property hyperspace compared to current experimental decoys.
- Pseudoisomers were demonstrated as a viable, low-cost option for VHTS validation.
- Developed and freely shared code to facilitate the generation of improved validation sets.
Conclusions:
- *In silico* isomerization is a powerful and cost-effective alternative for generating high-quality decoys for VHTS validation.
- This approach addresses critical shortcomings in current validation sets, particularly the dissimilarity between actives and decoys.
- The introduction of pseudoisomers further enhances the efficiency and affordability of VHTS validation set curation.
- The freely available code aims to advance the maturity and reliability of VHTS in drug discovery.
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