Allosteric small molecule modulators of nuclear receptors

Nuclear Receptors (NRs) are multi-domain proteins, whose natural regulation occurs via ligands for a classical, orthosteric, binding pocket and via intra- and inter-domain allosteric mechanisms. Allosteric modulation of NRs via synthetic small molecules has recently emerged as an interesting entry to address the need for small molecules targeting NRs in pathology, via novel modes of action and with beneficial profiles. In this review the general concept of allosteric modulation in drug discovery is first discussed, serving as a background and inspiration for NRs. Subsequently, the review focuses on examples of small molecules that allosterically modulate NRs, with a strong focus on structural information and the ligand binding domain. Recently discovered nanomolar potent allosteric site NR modulators are catapulting allosteric targeting of NRs to the center of attention. The obtained insights serve as a basis for recommendations for the next steps to take in allosteric small molecular targeting of NRs. [Display omitted] •Allosteric small molecule modulation has emerged as novel entry to targeting NRs.•Inspiration for allosteric NR modulation can be found in other receptor classes.•Allosteric NR modulators harbor the potential for providing novel NR pharmacology.•Screening assays focused on identifying allosteric NR modulators are needed.