Natural products have been the source of treatment for various human diseases from time immemorial. Interests in natural product‐based scaffolds for the discovery of modern drugs have grown in recent years. However, research on exploring the traditional medicinal systems for modern therapeutics is severely limited due to our incomplete understanding of the therapeutic mechanism of action. One possible solution is to develop computational approaches, based on ligand‐ and structure‐based screening tools, for fast and plausible target identification, leading to elucidation of the therapeutic mechanism. In the present work, we present two methods based on shape‐based and pharmacophore search to predict targets of natural products and elucidate their mechanism, and to identify natural product‐based leads. These methods were tested on an in‐house developed database of medicinal plants that include information from a largely unexplored North‐East region of India, known as one of the twelve mega biodiversity regions. However, depending on the choice of the lead molecules, any existing databases can be used for screening. MedPServer is an open access resource available at http://bif.uohyd.ac.in/medserver/.
Toll-like receptors (TLRs) activate host innate immunity by recognizing microbial ligands and viral nucleic acids. Of late, TLR8 has emerged as an attractive target for antiviral activity, antitumor activity and vaccine development owing to its ability to recognize small synthetic molecules that induce proinflammatory cytokines, type 1 interferons and chemokines. Of the many synthetic and natural ligands researched so far, ligands derived from coumarin have been known to have enhanced antiviral and immunomodulatory properties. Thus, the coumarin scaffold plays an important role through the modulation of cytokines by noncovalent interactions with various enzymes and receptors. The present study aims to identify a coumarin derivative that binds to the TLR8 receptor and induce NF-kB activity. In silico screening and chemical synthesis were performed to realize novel coumarin leads with potential TLR8 agonistic activity. HEK-Blue™ hTLR8 cell line was used to validate the TLR8 agonist evaluation In vitro. The key finding of this study brings out strong evidence supporting the binding of the 3,3 1 -(4 11 -N,N-dimethylaminophenylmethylene)-4,4 1 -epoxydicoumarin to TLR8 receptor in comparison to the co-crystallized R848 ligand.
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