Nuclear receptors (NRs) are a class of ligand-regulated transcription factors that can recruit coregulators and other transcription factors to gene promoters to influence tissue-specific transcriptomes. In this case, NRs are able to regulate the expression of specific genes and associated with various diseases, which makes them critical drug targets. As a first-class provider in the protein engineering fields, Creative Biolabs has developed several approaches to predict the inhibition ability of compounds for different NR targets which proves to be particularly helpful for drug development. Especially, our scientists can help clients to establish proteochemical modeling for pain and addiction to analyze the bioactivity between compounds and NR targets.

• NRs for Pain & Addiction Research

Addiction is a chronic disorder in which the consumption of a substance or behavior becomes compulsive and often recurrent. Drugs of abuse (e.g. opioids, alcohol, nicotine, cocaine, and amphetamines) affect the reward pathway in unique ways, resulting in the potential of addiction. The combination of pain and addiction is a complex, debilitating condition that is extremely difficult to treat owing to the likelihood of opioid dependence. Recent advances in chronic pain research have unraveled the biological complexity of the disorder and promoted the development of next-generation antidepressants, anti-inflammatory drugs, and anticonvulsant drugs to mitigate pains. More focus on developing small molecule drugs and biologics to target widely expressed pain NRs not only alleviate pain but also reduce abuse of opioid drugs.

• Structure-based NR Modeling Services at Creative Biolabs

Fig.2 Schematic representation of the structural domains of ER protein. (Ferrero, 2014)

NRs are essential targets for therapeutic drugs. They can modulate transcriptional activities through binding to ligands and interacting with several regulating proteins. Opioids are notorious for being addictive drugs. Animals deficient of estrogen receptors (ER, including ERα, ERβ) or GPR30 lack the estrogen-regulated opioid effects and thus display significant analgesic and addictive responses to morphine. Functional interactions between estrogens and opioids should be investigated to provide insight into pain and addiction at both cellular and physiological levels.

For example, X-ray structures have illustrated that the human ER binds ligands in a highly hydrophobic pocket which can accommodate chemical compounds of diverse sizes and properties. Due to local structural differences and conformational flexibility, these may, at least in principle, be exploited for the rational design of modified receptors capable of recognizing these compounds with different affinity and selectivity.

At Creative Biolabs, we’d like to introduce robust computational modeling methods that depend on the structure of ligand-receptor and protein-protein interactions. These, in turn, can facilitate the discovery of novel agonists and antagonists with high affinity and specificity as well as assisting in the prediction of side effects of drugs by identifying possible off-target effects. There’re some common NRs that can be used for pain and addiction research by structure-based modeling.

The limitations involved in the structural determination of NRs have been solved by using these sophisticated modeling protocols. Here, we provide computational approaches towards a number of clinically important NRs and study their use for screening toxic side effects of xenobiotics. In addition, our teams have the ability to predict NR mutants with altered binding properties by combining sequence alignment and structural analysis of known NR-ligand complexes with computational analysis.

• Highlights
  • Advanced computational modeling based on ligand- or receptor-based methods
  • Personalized support by our skillful technicians
  • A written report containing details of modeling and analytical data

Current revolution in the investigation of NRs using the latest structural and computational approaches has overturned its research paradigm. As a reliable partner in protein engineering services, Creative Biolabs provides comprehensive structure-based NR modeling strategies and pays attention to the process of method development and optimization to accept distinct receptor characters of NRs for pain and addiction research. The abundance of ligand-bound NR structures shows invaluable insights into the structure, function, and pharmacology of the receptors, enabling the application of structure-based drug design methods to aid in the discovery of promising candidates with improved pharmacological profiles. If you’re interested in any services, please don’t hesitate to contact usor directly send us an inquiry.

Reference

1. Ferrero, V.E.; et al. Rational modification of estrogen receptor by combination of computational and experimental analysis. PLoS One. 2014, 9(7): e102658.

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