Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 15, Pages -Publisher
MDPI
DOI: 10.3390/ijms23158732
Keywords
nuclear receptors; flexibility; drug design; agonists; antagonists; ligand binding domain
Funding
- University of Turin [SPY_RILO_ 20_01, SPY_RILO_21_01]
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Nuclear receptors (NRs) are transcription factors that play an important role in multiple diseases and their intrinsic dynamics make them a challenging target in drug discovery. This study proposes a methodology based on the computation and comparison of protein cavities in NR structures to uncover their dynamic profile. This approach can guide research on NR intrinsic dynamics, aid in selecting reference structures for drug design, and facilitate the identification of alternative binding sites.
Nuclear receptors (NRs) are transcription factors that play an important role in multiple diseases, such as cancer, inflammation, and metabolic disorders. They share a common structural organization composed of five domains, of which the ligand-binding domain (LBD) can adopt different conformations in response to substrate, agonist, and antagonist binding, leading to distinct transcription effects. A key feature of NRs is, indeed, their intrinsic dynamics that make them a challenging target in drug discovery. This work aims to provide a meaningful investigation of NR structural variability to outline a dynamic profile for each of them. To do that, we propose a methodology based on the computation and comparison of protein cavities among the crystallographic structures of NR LBDs. First, pockets were detected with the FLAPsite algorithm and then an all against all approach was applied by comparing each pair of pockets within the same sub-family on the basis of their similarity score. The analysis concerned all the detectable cavities in NRs, with particular attention paid to the active site pockets. This approach can guide the investigation of NR intrinsic dynamics, the selection of reference structures to be used in drug design and the easy identification of alternative binding sites.
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