J Chem Inf Model - How do 2D fingerprints detect structurally diverse active compounds? Revealing compound subset-specific fingerprint features through systematic selection.

Tópicos

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Resumo

In independent studies it has previously been demonstrated that two-dimensional (2D) fingerprints have scaffold hopping ability in virtual screening, although these descriptors primarily emphasize structural and/or topological resemblance of reference and database compounds. However, the mechanism by which such fingerprints enrich structurally diverse molecules in database selection sets is currently little understood. In order to address this question, similarity search calculations on 120 compound activity classes of varying structural diversity were carried out using atom environment fingerprints. Two feature selection methods, Kullback-Leibler divergence and gain ratio analysis, were applied to systematically reduce these fingerprints and generate alternative versions for searching. Gain ratio is a feature selection method from information theory that has thus far not been considered in fingerprint analysis. However, it is shown here to be an effective fingerprint feature selection approach. Following comparative feature selection and similarity searching, the compound recall characteristics of original and reduced fingerprint versions were analyzed in detail. Small sets of fingerprint features were found to distinguish subsets of active compounds from other database molecules. The compound recall of fingerprint similarity searching often resulted from a cumulative detection of distinct compound subsets by different fingerprint features, which provided a rationale for the scaffold hopping potential of these 2D fingerprints.

Resumo Limpo

independ studi previous demonstr twodimension d fingerprint scaffold hop abil virtual screen although descriptor primarili emphas structur andor topolog resembl refer databas compound howev mechan fingerprint enrich structur divers molecul databas select set current littl understood order address question similar search calcul compound activ class vari structur divers carri use atom environ fingerprint two featur select method kullbackleibl diverg gain ratio analysi appli systemat reduc fingerprint generat altern version search gain ratio featur select method inform theori thus far consid fingerprint analysi howev shown effect fingerprint featur select approach follow compar featur select similar search compound recal characterist origin reduc fingerprint version analyz detail small set fingerprint featur found distinguish subset activ compound databas molecul compound recal fingerprint similar search often result cumul detect distinct compound subset differ fingerprint featur provid rational scaffold hop potenti d fingerprint

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