scholarly journals OcUGT1-Catalyzing Glycodiversification of Steroids through Glucosylation and Transglucosylation Actions

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 475
Author(s):  
Yan-Li Xu ◽  
Jian-Qiang Kong
Keyword(s):  
Uridine Diphosphate ◽  
Efficient Approach ◽  
Multifunctional Enzyme ◽  
Steroidal Glycosides ◽  
Lead Compounds ◽  
Innovative Drugs ◽  
Ornithogalum Caudatum

Steroidal glycosides are important sources of innovative drugs. The increased diversification of steroidal glycosides will expand the probability of discovering active molecules. It is an efficient approach to diversify steroidal glycosides by using steroidal glycosyltransferases. OcUGT1, a uridine diphosphate-d-glucose (UDP-Glc)-dependent glycosyltransferase from Ornithogalum caudatum, is a multifunctional enzyme, and its glycodiversification potential towards steroids has never been fully explored. Herein, the glycodiversification capability of OcUGT1 towards 25 steroids through glucosylation and transglucosylation reactions were explored. Firstly, each of 25 compounds was glucosylated with UDP-Glc. Under the action of OcUGT1, five steroids (testosterone, deoxycorticosterone, hydrocortisone, estradiol, and 4-androstenediol) were glucosylated to form corresponding mono-glucosides and biosides. Next, OcUGT1-mediated transglucosylation activity of these compounds with another sugar donor ortho-nitrophenyl-β-d-glucopyranoside (oNPGlc) was investigated. Results revealed that the same five steroids could be glucosylated to generate mono-glucosides and biosides by OcUGT1 through transglucosylation reactions. These data indicated that OcUGT1-assisted glycodiversification of steroids could be achieved through glucosylation and transglucosylation reactions. These results provide a way to diversify steroidal glycosides, which lays the foundation for the increase of the probability of obtaining active lead compounds.

scholarly journals Inhibition of Thioredoxin Reductase by Santamarine Conferring Anticancer Effect in HeLa Cells

2021 ◽  
Vol 8 ◽  
Author(s):  
Junmin Zhang ◽  
Qianhe Xu ◽  
Hong-Ying Yang ◽  
Minghao Yang ◽  
Jianguo Fang ◽  
...  
Keyword(s):  
Thioredoxin Reductase ◽  
Structural Diversity ◽  
Physiological Effect ◽  
Anticancer Effect ◽  
Antioxidative Function ◽  
Lead Compounds ◽  
Action Mechanisms ◽  
Innovative Drugs ◽  
Further Development ◽  
Potential Cancer

Natural products frequently have unique physiological activities and new action mechanisms due to their structural diversity and novelty, and are an important source for innovative drugs and lead compounds. We present herein that natural product santamarine targeted thioredoxin reductase (TrxR) to weaken its antioxidative function in cells, accompanied by accumulation of high levels of reactive oxygen species (ROS), and finally induced a new mechanism of tumor cell oxidative stress-mediated apoptosis. TrxR knockdown or overexpression cell lines were employed to further evaluate the cytotoxicity of santamarine regulated by TrxR, demonstrated that TrxR played a key role in the physiological effect of santamarine on cells. Santamarine targeting TrxR reveals its previously unrecognized mechanism of antitumor and provides a basis for the further development of santamarine as a potential cancer therapeutic agent.

scholarly journals Structure-Based Virtual Screening of Pseudomonas aeruginosa LpxA Inhibitors using Pharmacophore-Based Approach

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 266
Author(s):  
Baki Vijaya Bhaskar ◽  
Tirumalasetty Muni Chandra Babu ◽  
Aluru Rammohan ◽  
Gui Yu Zheng ◽  
Grigory V. Zyryanov ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Virtual Screening ◽  
Lipid A ◽  
Catalytic Mechanism ◽  
Pharmacophore Model ◽  
Selective Inhibition ◽  
Binding Pocket ◽  
Uridine Diphosphate ◽  
Lead Compounds ◽  
Essential Enzyme

Multidrug resistance in Pseudomonas aeruginosa is a noticeable and ongoing major obstacle for inhibitor design. In P. aeruginosa, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) acetyltransferase (PaLpxA) is an essential enzyme of lipid A biosynthesis and an attractive drug target. PaLpxA is a homotrimer, and the binding pocket for its substrate, UDP-GlcNAc, is positioned between the monomer A–monomer B interface. The uracil moiety binds at one monomer A, the GlcNAc moiety binds at another monomer B, and a diphosphate form bonds with both monomers. The catalytic residues are conserved and display a similar catalytic mechanism across orthologs, but some distinctions exist between pocket sizes, residue differences, substrate positioning and specificity. The analysis of diversified pockets, volumes, and ligand positions was determined between orthologues that could aid in selective inhibitor development. Thenceforth, a complex-based pharmacophore model was generated and subjected to virtual screening to identify compounds with similar pharmacophoric properties. Docking and general Born-volume integral (GBVI) studies demonstrated 10 best lead compounds with selective inhibition properties with essential residues in the pocket. For biological access, these scaffolds complied with the Lipinski rule, no toxicity and drug likeness properties, and were considered as lead compounds. Hence, these scaffolds could be helpful for the development of potential selective PaLpxA inhibitors.

scholarly journals Pangenome Analysis of Mycobacterium tuberculosis Reveals Core-Drug Targets and Screening of Promising Lead Compounds for Drug Discovery

Antibiotics ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 819
Author(s):  
Hamza Arshad Dar ◽  
Tahreem Zaheer ◽  
Nimat Ullah ◽  
Syeda Marriam Bakhtiar ◽  
Tianyu Zhang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Drug Targets ◽  
Uridine Diphosphate ◽  
Lead Compounds ◽  
Diphosphate Glucose ◽  
Inhibitory Potential ◽  
Conserved Core ◽  
Effective Drugs ◽  
Novel Drug

Tuberculosis, caused by Mycobacterium tuberculosis (M. tuberculosis), is one of the leading causes of human deaths globally according to the WHO TB 2019 report. The continuous rise in multi- and extensive-drug resistance in M. tuberculosis broadens the challenges to control tuberculosis. The availability of a large number of completely sequenced genomes of M. tuberculosis has provided an opportunity to explore the pangenome of the species along with the pan-phylogeny and to identify potential novel drug targets leading to drug discovery. We attempt to calculate the pangenome of M. tuberculosis that comprises a total of 150 complete genomes and performed the phylo-genomic classification and analysis. Further, the conserved core genome (1251 proteins) is subjected to various sequential filters (non-human homology, essentiality, virulence, physicochemical parameters, and pathway analysis) resulted in identification of eight putative broad-spectrum drug targets. Upon molecular docking analyses of these targets with ligands available at the DrugBank database shortlisted a total of five promising ligands with projected inhibitory potential; namely, 2′deoxy-thymidine-5′-diphospho-alpha-d-glucose, uridine diphosphate glucose, 2′-deoxy-thymidine-beta-l-rhamnose, thymidine-5′-triphosphate, and citicoline. We are confident that with further lead optimization and experimental validation, these lead compounds may provide a sound basis to develop safe and effective drugs against tuberculosis disease in humans.

Electrolytic Lead Compounds

1909 ◽  
Vol 67 (1744supp) ◽  
pp. 367-367
Author(s):  
Carl Duvivier
Keyword(s):  
Lead Compounds

Marine endoperoxides as antiprotozoan lead compounds

Planta Medica ◽  
2012 ◽  
Vol 78 (11) ◽  
Author(s):  
G Chianese ◽  
E Fattorusso ◽  
C Fattorusso ◽  
M Persico ◽  
D Taramelli ◽  
...  
Keyword(s):  
Lead Compounds

Structure and cytotoxicity of steroidal glycosides from Allium schoenoprasum

Planta Medica ◽  
2012 ◽  
Vol 78 (11) ◽  
Author(s):  
G Timité ◽  
AC Mitaine-Offer ◽  
T Miyamoto ◽  
C Tanaka ◽  
JF Mirjolet ◽  
...  
Keyword(s):  
Steroidal Glycosides ◽  
Allium Schoenoprasum

Discovery of anticancer lead compounds from plants of Vietnam

Planta Medica ◽  
2014 ◽  
Vol 80 (10) ◽  
Author(s):  
D Djendoel Soejarto ◽  
L Bueno Pérez ◽  
Y Ren ◽  
L Pan ◽  
U Muñoz Acuña ◽  
...  
Keyword(s):  
Lead Compounds

New steroidal glycosides from Dracaena marginata, Dracaena fragrans and Allium flavum

Planta Medica ◽  
2014 ◽  
Vol 80 (16) ◽  
Author(s):  
A Rezgui ◽  
AC Mitaine-Offer ◽  
T Miyamoto ◽  
C Tanaka ◽  
T Paululat ◽  
...  
Keyword(s):  
Steroidal Glycosides
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