Structure-based Nuclear Receptors Modeling

Nuclear receptors (NRs) are important targets for therapeutic drugs. NRs regulate transcriptional activities through binding to ligands and interacting with a number of regulating proteins. Computational methods can provide insights into essential ligand-receptor and protein-protein interactions. Creative Biolabs has focused on the development of computational pharmacology services for many years and has established excellent platforms for drug development. We provide a variety of nuclear receptors modeling services to meet the diverse needs of our customers.

Introduction to Structure-based Nuclear Receptors Modeling

Phylogenetic analysis of NRs paved the way for the classification of this superfamily based on evolutionary sequence conservation observed among different receptors. To date, the receptors have diverged into six subfamilies. Nearly all NRs contain two well-defined structural domains: a DNA-binding domain (DBD) that resides approximately along the center of the polypeptides and a ligand-binding domain (LBD) positioned along the C-terminal 200-300 residues. The DBD and LBD are linked via a hinge region that is also variable and often contains DNA minor groove binding residues positioned just C-terminal to the DBD, referred to as C-terminal extensions (CTEs). The LBD has been the main focus for drug discovery, as it is the site that ligands bind to and coactivator-derived motifs interact with.

Different computational methods have emerged aimed at understanding and modeling the functional activities of NR modulators at the molecular level. Generally, these computational approaches fall into two categories, ligand-based and structure-based approaches. Ligand-based methods essentially focus on molecular similarity, which implies that molecules with similar features exhibit similar biological responses. In contrast, structure-based methods require the three-dimensional structure of the protein targets predominantly generated from X-ray crystallography, NMR structures or homology modeling, in order to address the fundamental question of how a potential ligand might bind to the receptor. The structure-based strategies have been widely applied to advance the understanding of various aspects of pharmacology in NRs.

Structure-based pharmacophores modeling and screening. Fig.1 Domain structures of NRs and mechanism of action upon ligand binding.

Services

NRs represent one of the most important targets for therapeutic interventions for multiple diseases, including cancer, inflammation, and metabolic diseases. It is therefore important to identify synthetic compounds that mimic the cognate NR ligand activity, and to develop synthetic compounds that selectively modulate the pharmacology of NRs in a cell-type and/or tissue-selective manner to exert the desired therapeutic effects. Structure-based methods have been employed to understand the structural basis for recognition and specificity among interacting partners that are required for precise regulation of transcriptional activities of NRs. In addition, computational analysis of three-dimensional coordinates of protein structures has helped identify evolutionary important residues and correlated them with important NR functions, such as dimerization and DNA binding.

At Creative Biolabs, we can provide a variety of structure-based NRs modeling approaches to meet customers’ specific requirements.

Creative Biolabs has focused on the development of computational pharmacology for years. Now, we whole-heartedly cooperate with you to accomplish our shared goals. Our team provides you with outstanding support and meets your specific needs with a professional technology platform. If you are interested in our services, please contact us for more details.

All listed services and products are For Research Use Only. Do Not use in any diagnostic or therapeutic applications.

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