In order to discover the molecular scaffold of a class of molecules such as NR-inhibitors, massive structure of molecules with bioactivity need to be screened and clustered to finding the consensus structure domain. In that case, finding novel bioactive scaffolds is an essential process in the area of drug design. It can be noticed that finding a new scaffold often lead to the discovery of a new inhibitor classes which may have the potential to become future drugs. Therefore, scaffold based strategies were widely used for drug discovery. In drug design, scaffold is the fixed part of a molecule which is the essential part for biological activity of molecule. In that case, discover novel drugs as nuclear receptor inhibitors have acquired a particular significance for NR-related metabolic diseases treatment. Meanwhile, over 13% FDA approved drugs were aimed at those nuclear receptors. Till now, 48 nuclear receptors have been discovered in humans, 23 of them are certified as drug target by U.S. Since NR can affect the expression of enormous genes which associated with various diseases such as diabetes and hepatic adipose infiltration, it can be considered as an appropriate therapeutic target for new drug discovery. After activation, NR can regulate the expression of specific genes and then participate in several essential physiological processes such as development, homeostasis and metabolism of the organism. Generally, the methods and molecular scaffolds proposed in this article can not only help the screening of potential therapeutic NR-inhibitors but also able to guide the future NR-related drug discovery.Īs a ligand dependent transcription factors, nuclear receptors (NR) can be activated by important molecules such as steroidal hormones, endogenous hormones, glucocorticoids and thyroid hormones. Through scaffolds analysis, those essential bioactive scaffolds of different NR target can be detected and compared. Moreover, in-silico predicted bioactive compounds were clustered according to structure similarity and a series of representative molecular scaffolds can be derived for five major NR targets. Results illustrated the ability of our PCM model for high-throughput NR-inhibitor screening after evaluated on both internal (AUC > 0.870) and external (AUC > 0.746) validation set. In this study, proteochemometric modelling was introduced to analysis the bioactivity between chemical compounds and NR targets. Approaches which can predict the inhibition ability of compounds for different NR target should be particularly helpful for drug development. In that case, NR have the ability to regulate the expression of specific genes and associated with various diseases, which make it essential drug targets. Nuclear receptors (NR) are a class of proteins that are responsible for sensing steroid and thyroid hormones and certain other molecules.
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