“Bayes Affinity Fingerprints” Improve Retrieval Rates in Virtual Screening and Define Orthogonal Bioactivity Space:  When Are Multitarget Drugs a Feasible Concept?

Conventional similarity searching of molecules compares single (or multiple) active query structures to each other in a relative framework, by means of a structural descriptor and a similarity measure. While this often works well, depending on the target, we show here that retrieval rates can be improved considerably by incorporating an external framework describing ligand bioactivity space for comparisons ("Bayes affinity fingerprints"). Structures are described by Bayes scores for a ligand panel comprising about 1000 activity classes extracted from the WOMBAT database. The comparison of structures is performed via the Pearson correlation coefficient of activity classes, that is, the order in which two structures are similar to the panel activity classes. Compound retrieval on a recently published data set could be improved by as much as 24% relative (9% absolute). Knowledge about the shape of the "bioactive chemical universe" is thus beneficial to identifying similar bioactivities. Principal component analysis was employed to further analyze activity space with the objective to define orthogonal ligand bioactive chemical space, leading to nine major (roughly orthogonal) activity axes. Employing only those nine activity classes, retrieval rates are still comparable to original Bayes affinity fingerprints; thus, the concept of orthogonal bioactive ligand chemical space was validated as being an information-rich but low-dimensional representation of bioactivity space. Correlations between activity classes are a major determinant to gauge whether the desired multitarget activity of drugs is (on the basis of current knowledge) a feasible concept because it measures the extent to which activities can be optimized independently, or only by strongly influencing one another.