Navigations of Chemical Space to Further the Understanding of Polypharmacology in Human Nuclear Receptors

Recent years have seen an increasing awareness that drugs often bind to more than one molecular target, exhibiting polypharmacology. Although this aspect has commonly been considered as undesirable, promiscuity being responsible for unwanted side effects, in many cases it is a key component of the therapeutic efficacy of drugs. Nuclear receptors (NRs) are ligand-dependent transcription factors that offer important druggable targets for therapeutic interventions in multiple disease areas. Many NRs are promiscuous with respect to the wide range of ligands that act as modulators, and many NR modulators are not specific with respect to the number of NRs they bind. In this article, we aim to investigate aspects of ligand polypharmacology in the superfamily of human NRs. To this end, the construction of a target-centric and a ligand-centric chemical space is first discussed as instrumental in charting geometrical and physicochemical properties of NR binding sites and cognate ligands that, being characteristic of specific groups of receptors and/or modulators, could underlie their promiscuity. In the second part of the work, generating a graph network, we depict relationships among geometrical and physicochemical properties of binding sites that are used to infer aspects of polypharmacology in human NRs. Working hypotheses of NR ligand polypharmacology are thus generated and discussed in the light of case studies found in the literature.