Please use this identifier to cite or link to this item: https://doi.org/10.1021/np5007179
Title: Specificity and Inhibitory Mechanism of Andrographolide and Its Analogues as Antiasthma Agents on NF-kappa B p50
Authors: Van, Sang Nguyen 
Loh, Xin Yi 
Wijaya, Hadhi 
Wang, Jigang 
Lin, Qingsong 
Lam, Yulin 
Wong, Wai-Shiu Fred 
Mok, Yu Keung 
Keywords: Science & Technology
Life Sciences & Biomedicine
Plant Sciences
Chemistry, Medicinal
Pharmacology & Pharmacy
DNA-BINDING
COVALENT MODIFICATION
CRYSTAL-STRUCTURE
IN-VITRO
INFLAMMATION
HETERODIMER
ACTIVATION
REACTIVITY
MEDIATORS
PROTEINS
Issue Date: 1-Feb-2015
Publisher: AMER CHEMICAL SOCIETY
Citation: Van, Sang Nguyen, Loh, Xin Yi, Wijaya, Hadhi, Wang, Jigang, Lin, Qingsong, Lam, Yulin, Wong, Wai-Shiu Fred, Mok, Yu Keung (2015-02-01). Specificity and Inhibitory Mechanism of Andrographolide and Its Analogues as Antiasthma Agents on NF-kappa B p50. JOURNAL OF NATURAL PRODUCTS 78 (2) : 208-217. ScholarBank@NUS Repository. https://doi.org/10.1021/np5007179
Abstract: © 2015 The American Chemical Society and American Society of Pharmacognosy. Andrographolide (1) is a diterpenoid lactone with an α,β-unsaturated lactone group that inhibits NF-κB DNA binding. Andrographolide reacts with the nucleophilic Cys62 of NF-κB p50 through a Michael addition at the Δ12(13) exocylic double bond to form a covalent adduct. Using computer docking, site-directed mutagenesis, and mass spectrometry, the noncovalent interactions between andrographolide and additional binding site residues other than Cys62 were found to be essential for the covalent incorporation of andrographolide. Furthermore, the addition reaction of andrographolide on Cys62 was highly dependent on the redox conditions and on the vicinity of nearby, positively charged Arg residues in the conserved RxxRxR motif. The reaction mechanisms of several of the analogues were determined, showing that 14-deoxy-11,12-didehydroandrographolide (8) reacts with NF-κB p50 via a novel mechanism distinct from andrographolide. The noncovalent interaction and redox environment of the binding site should be considered, in addition to the electrophilicity, when designing a covalent drug. Analogues similar in structure appear to use distinct reaction mechanisms and may have very different cytotoxicities, e.g., compound 6.
Source Title: JOURNAL OF NATURAL PRODUCTS
URI: https://scholarbank.nus.edu.sg/handle/10635/168890
ISSN: 01633864
15206025
DOI: 10.1021/np5007179
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