Hierarchical Bayesian Modeling of Pharmacophores in Bioinformatics

Summary One of the key ingredients in drug discovery is the derivation of conceptual templates called pharmacophores. A pharmacophore model characterizes the physicochemical properties common to all active molecules, called ligands, bound to a particular protein receptor, together with their relative spatial arrangement. Motivated by this important application, we develop a Bayesian hierarchical model for the derivation of pharmacophore templates from multiple configurations of point sets, partially labeled by the atom type of each point. The model is implemented through a multistage template hunting algorithm that produces a series of templates that capture the geometrical relationship of atoms matched across multiple configurations. Chemical information is incorporated by distinguishing between atoms of different elements, whereby different elements are less likely to be matched than atoms of the same element. We illustrate our method through examples of deriving templates from sets of ligands that all bind structurally related protein active sites and show that the model is able to retrieve the key pharmacophore features in two test cases.