Improved Virtual Screening Strategies and Enrichment of Focused Libraries in Active Compounds Using Target-Oriented Databases
Aureus Pharma has constituted and maintains a unique and comprehensive database regrouping all the data already published on GPCR and Ion channel medicinal chemistry and pharmacology. Chemical structures of ligands (> 150,000) as well as precise description of their targets and of all type of in vitro and in vivo pharmacological responses (> 600,000) have been collected from more than 20,000 published references. A specific software has been designed to query the database using biological keys as well as chemical features. Substructure and similarity search within the database has been implemented through the integration of J Chem within the query tool. In the present work, we illustrate the superiority of hit identification and focused library design when a virtual screening approach uses a highly documented source of knowledge and a high performance fingerprint calculation and comparison software;. In our strategy, biological filters (queries) are used to identify training sets of active compounds. The virtual screening done using ChemAxon tools uses these training sets to constitute “chemical” filters to screen compound catalogs. This method was applied to NK1-specific ligands. The vast amount of data regrouped in Aureus Pharma AurSCOPE database allows us to enrich and increase the diversity of a query set, yielding higher hit rates. The used pharmacophoric fingerprints appear to give rise to structurally diverse series of hit compounds and a better enrichment ratio. We demonstrate that 2D chemical and pharmacophoric fingerprints lead to considerable improvement in the design of focused libraries.