Amide Conformational Switching Induced by Protonation of Aromatic Substituent

2003 ◽  
Vol 5 (8) ◽  
pp. 1265-1267 ◽  
Author(s):  
Ryu Yamasaki ◽  
Aya Tanatani ◽  
Isao Azumaya ◽  
Shoichi Saito ◽  
Kentaro Yamaguchi ◽  
...  
Keyword(s):  
Conformational Switching ◽  
Aromatic Substituent

Synthesis, Characterization and In vitro Evaluation of N-Substituted- Sulfomoyl-Phenyl-Amino Carboxylic Acid Derivatives as Squalene Synthase Inhibitors

2019 ◽  
Vol 15 (4) ◽  
pp. 415-426
Author(s):  
Avani B. Chokshi ◽  
Mahesh T. Chhabria ◽  
Pritesh R. Desai
Keyword(s):  
Carboxylic Acid ◽  
Cell Line ◽  
Hepatic Cell ◽  
Squalene Synthase ◽  
Lipid Lowering ◽  
Assay Method ◽  
Aromatic Substituent ◽  
Hepatic Cell Line ◽  
Amino Carboxylic Acid

Background:Squalene Synthase is one of the cholesterol biosynthetic pathway enzymes, inhibition of which produces potent lipid lowering action. A variety of chemical classes have been evaluated for its inhibition to provide alternate antihyperlipidemic agents to statins.Methods:A series of N-substituted-sulfomoyl-phenyl-amino carboxylic acid derivatives were designed through pharmacophore modelling as Squalene Synthase inhibitors. We report here the synthesis, characterization and in vitro pharmacological screening of the designed molecules as Squalene synthase inhibitors. The target molecules were synthesized by a simple procedure and each molecule was characterized by IR, Mass, 1HNMR and 13CNMR spectroscopic techniques. As a primary site of action for cholesterol biosynthesis is liver, each of the molecules were first screened for in vitro cytotoxicity over human hepatic cell line (HepG2) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay method. The enzyme inhibition assay was performed on cell lysates prepared from HepG2 cells by Human Squalene Synthase ELISA kit, where test compounds were added in the nontoxic concentrations only.Results:Compound 5f was found to be most potent with the IC50 value of 11.91 µM. The CTC50 value for 5f on human hepatic cell line was > 1000 µM so it was considered that the compound was relatively safe and might be free of hepatotoxicity.Conclusion:From the results of our studies, it was observed that compounds with poly nuclear aromatic or hetero aromatic substituent on a side chain were more potent enzyme inhibitors and a distance of 4-5 atoms is optimum between amide nitrogen and hydroxyl group of carboxylic acid.

scholarly journals Tuning flavin environment to detect and control light-induced conformational switching in Drosophila cryptochrome

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Siddarth Chandrasekaran ◽  
Connor M. Schneps ◽  
Robert Dunleavy ◽  
Changfan Lin ◽  
Cristina C. DeOliveira ◽  
...  
Keyword(s):  
Side Reactions ◽  
Resonance Spectroscopy ◽  
Conformational Switching ◽  
Spin Resonance ◽  
Degradation Activity ◽  
Recognition Motifs ◽  
Cellular Turnover ◽  
Control Light ◽  
Dynamics Simulations ◽  
And Control

AbstractLight-induction of an anionic semiquinone (SQ) flavin radical in Drosophila cryptochrome (dCRY) alters the dCRY conformation to promote binding and degradation of the circadian clock protein Timeless (TIM). Specific peptide ligation with sortase A attaches a nitroxide spin-probe to the dCRY C-terminal tail (CTT) while avoiding deleterious side reactions. Pulse dipolar electron-spin resonance spectroscopy from the CTT nitroxide to the SQ shows that flavin photoreduction shifts the CTT ~1 nm and increases its motion, without causing full displacement from the protein. dCRY engineered to form the neutral SQ serves as a dark-state proxy to reveal that the CTT remains docked when the flavin ring is reduced but uncharged. Substitutions of flavin-proximal His378 promote CTT undocking in the dark or diminish undocking in the light, consistent with molecular dynamics simulations and TIM degradation activity. The His378 variants inform on recognition motifs for dCRY cellular turnover and strategies for developing optogenetic tools.

Molecular Mechanism of Light-Induced Conformational Switching of the LOV Domain in Aureochrome-1

Biochemistry ◽  
2020 ◽  
Vol 59 (28) ◽  
pp. 2592-2601 ◽  
Author(s):  
Itsuki Kobayashi ◽  
Hiroto Nakajima ◽  
Osamu Hisatomi
Keyword(s):  
Molecular Mechanism ◽  
Lov Domain ◽  
Conformational Switching

Actuated Conformational Switching in a Single Crystal of a Homodithiacalix[4]arene

2013 ◽  
Vol 52 (39) ◽  
pp. 10237-10240 ◽  
Author(s):  
Joice Thomas ◽  
Gunter Reekmans ◽  
Peter Adriaensens ◽  
Luc Van Meervelt ◽  
Mario Smet ◽  
...  
Keyword(s):  
Single Crystal ◽  
Conformational Switching

scholarly journals Interaction of the ASAP1 PH Domain with the N Terminus of ARF1 is Controlled by Conformational Switching

2018 ◽  
Vol 114 (3) ◽  
pp. 405a
Author(s):  
Neeladri S. Roy ◽  
Peng Zhai ◽  
Xiaoying Jian ◽  
Lisa Jenkins ◽  
Ruibai Luo ◽  
...  
Keyword(s):  
Ph Domain ◽  
Conformational Switching ◽  
N Terminus

scholarly journals Conformational switching in single crystals of a calix[4]resorcinarene

2019 ◽  
Vol 75 (a2) ◽  
pp. e479-e479
Author(s):  
Saber Mirzaei ◽  
Qadir Timerghazin ◽  
Sergey Lindeman
Keyword(s):  
Single Crystals ◽  
Conformational Switching
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