Ribocil
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| IUPAC name
2-[1-[[2-(methylamino)pyrimidin-5-yl]methyl]piperidin-3-yl]-4-thiophen-2-yl-1H-pyrimidin-6-one
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3D model (JSmol)
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PubChem CID
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| Properties | |
| C19H22N6OS | |
| Molar mass | 382.49 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references
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Ribocil is chemical compound which is found to be a potent inhibitor of the FMN riboswitch, meaning it could serve as a promising lead compound for developing a new antibiotic class. The compound was discovered by Merck & Co. through a phenotypic screen of the Gram-positive bacteria Staphylococcus aureus.[1] The binding mode of this small molecule to its binding site has been confirmed through the use of X-Ray crystallography.[2]
Binding mode
The structure of ribocil versus previously discovered binders to the FMN riboswitch makes it unique, as it is not a structural analogue to the natural ligand, flavin mononucleotide (FMN). The binding mode of this compound has some similarities with ribocil, where the same π-π stacking interaction and two hydrogen bond is also conserved. Ribocil also makes two new contacts with the binding site which notably differs from FMN: a π-π interaction between the aminopyrimidine of ribocil and residue G62 and an edge-face π-interaction.[2]
Challenges and derivatives
One major obstacle of using ribocil as a bona fide antibiotic is that although it kills bacteria in culture, Gram-positive organisms can scavenge riboflavin from their environment.[3] While ribocil in itself has no activity towards Gram-negative bacteria, derivatives of ribocil which enhance the accumulative properties of these compounds have been synthesized to show whole-cell activity against wild-type strains of these bacteria.[1][3][4]
References
- ^ a b Howe, John A.; Wang, Hao; Fischmann, Thierry O.; Balibar, Carl J.; Xiao, Li; Galgoci, Andrew M.; Malinverni, Juliana C.; Mayhood, Todd; Villafania, Artjohn; Nahvi, Ali; Murgolo, Nicholas; Barbieri, Christopher M.; Mann, Paul A.; Carr, Donna; Xia, Ellen; Zuck, Paul; Riley, Dan; Painter, Ronald E.; Walker, Scott S.; Sherborne, Brad; de Jesus, Reynalda; Pan, Weidong; Plotkin, Michael A.; Wu, Jin; Rindgen, Diane; Cummings, John; Garlisi, Charles G.; Zhang, Rumin; Sheth, Payal R.; Gill, Charles J.; Tang, Haifeng; Roemer, Terry (2015-10-29). "Selective small-molecule inhibition of an RNA structural element". Nature. 526 (7575): 672–677. Bibcode:2015Natur.526..672H. doi:10.1038/nature15542. ISSN 0028-0836. PMID 26416753. Retrieved 2017-02-02.
- ^ a b Howe, John A.; Xiao, Li; Fischmann, Thierry O.; Wang, Hao; Tang, Haifeng; Villafania, Artjohn; Zhang, Rumin; Barbieri, Christopher M.; Roemer, Terry (2016-10-02). "Atomic resolution mechanistic studies of ribocil: A highly selective unnatural ligand mimic of the E. coli FMN riboswitch". RNA Biology. 13 (10): 946–954. doi:10.1080/15476286.2016.1216304. ISSN 1547-6286. PMC 5056776. PMID 27485612. Retrieved 2020-09-08.
- ^ a b Wang, Hao; Mann, Paul A.; Xiao, Li; Gill, Charles; Galgoci, Andrew M.; Howe, John A.; Villafania, Artjohn; Barbieri, Christopher M.; Malinverni, Juliana C.; Sher, Xinwei; Mayhood, Todd; McCurry, Megan D.; Murgolo, Nicholas; Flattery, Amy; Mack, Matthias (2017-05-18). "Dual-Targeting Small-Molecule Inhibitors of the Staphylococcus aureus FMN Riboswitch Disrupt Riboflavin Homeostasis in an Infectious Setting". Cell Chemical Biology. 24 (5): 576–588.e6. doi:10.1016/j.chembiol.2017.03.014. ISSN 2451-9456. PMID 28434876.
- ^ Motika, Stephen E.; Ulrich, Rebecca J.; Geddes, Emily J.; Lee, Hyang Yeon; Lau, Gee W.; Hergenrother, Paul J. (2020-06-17). "Gram-Negative Antibiotic Active Through Inhibition of an Essential Riboswitch". Journal of the American Chemical Society. 142 (24): 10856–10862. Bibcode:2020JAChS.14210856M. doi:10.1021/jacs.0c04427. ISSN 0002-7863. PMC 7405991. PMID 32432858.