scholarly journals Identification of potential inhibitors for AIRS from de novo purine biosynthesis pathway through molecular modeling studies – a computational approach

2016 ◽  
Vol 34 (10) ◽  
pp. 2199-2213 ◽  
Author(s):  
R. Guru Raj Rao ◽  
Jayashree Biswal ◽  
Prabhu Dhamodharan ◽  
Surekha Kanagarajan ◽  
Jeyakanthan Jeyaraman
Keyword(s):  
Molecular Modeling ◽  
De Novo ◽  
Computational Approach ◽  
Purine Biosynthesis ◽  
Biosynthesis Pathway ◽  
De Novo Purine Biosynthesis ◽  
Modeling Studies ◽  
Molecular Modeling Studies ◽  
Potential Inhibitors

In Silico Structure Modeling and Molecular Docking Analysis of Phosphoribosyl Pyrophosphate Amidotransferase (PPAT) with Antifolate Inhibitors

2019 ◽  
Vol 19 (5) ◽  
pp. 408-416 ◽  
Author(s):  
Nousheen Bibi ◽  
Zahida Parveen ◽  
Muhammad Sulaman Nawaz ◽  
Mohammad Amjad Kamal
Keyword(s):  
Hydrogen Bonding ◽  
Molecular Docking ◽  
Active Site ◽  
Electrostatic Interactions ◽  
De Novo ◽  
Cancer Therapeutics ◽  
Purine Biosynthesis ◽  
Biosynthesis Pathway ◽  
Phosphoribosyl Pyrophosphate ◽  
De Novo Purine Biosynthesis

Background: Cancer remains one of the most serious disease worldwide. Robust metabolism is the hallmark of cancer. PPAT (phosphoribosyl pyrophosphate amidotransferase) catalyzes the first committed step of de novo purine biosynthesis. Hence PPAT, the key regulatory spot in De novo purine nucleotide biosynthesis, is an attractive and credible drug target for leukemia and other cancer therapeutics. Objective: In the present study, detailed computational analysis has been performed for PPAT protein, the key enzyme in de novo purine biosynthesis which is inhibited by many folate derivatives, hence we aimed to investigate and gauge the inhibitory effect of antifolate derivatives; lomexterol (LTX) methotrexate (LTX), and pipretixin (PTX) with human PPAT to effectively capture and inhibit De novo purine biosynthesis pathway. Methods: The sequence to structure computational approaches followed by molecular docking experiments was performed to gain insight into the inhibitory mode, binding orientation and binding affinities of selected antifolate derivatives against important structural features of PPAT. Results: Results indicated a strong affinity of antifolate inhibitors for the conserved active site of PPAT molecule encompassing a number of hydrophobic, hydrogen bonding, Vander Waals and electrostatic interactions. Results: Results indicated a strong affinity of antifolate inhibitors for the conserved active site of PPAT molecule encompassing a number of hydrophobic, hydrogen bonding, Vander Waals and electrostatic interactions. Conclusion: Conclusively, the strong physical interaction of selected antifolate inhibitors with human PPAT suggests the selective inhibition of De novo purine biosynthesis pathway by antifolate derivatives towards cancer therapeutics.

scholarly journals The de novo Purine Biosynthesis Pathway Is the Only Commonly Regulated Cellular Pathway during Biofilm Formation in TSB-Based Medium in Staphylococcus aureus and Enterococcus faecalis

2021 ◽  
Keyword(s):  
Staphylococcus Aureus ◽  
Enterococcus Faecalis ◽  
Biofilm Formation ◽  
De Novo ◽  
Purine Biosynthesis ◽  
Biosynthesis Pathway ◽  
Chronic Infections ◽  
De Novo Purine Biosynthesis ◽  
Cellular Pathways ◽  
Different Strains

Bacterial biofilms are involved in chronic infections and confer 10 to 1,000 times more resistance to antibiotics compared with planktonic growth, leading to complications and treatment failure. When transitioning from a planktonic lifestyle to biofilms, some Gram-positive bacteria are likely to modulate several cellular pathways, including central carbon metabolism, biosynthesis pathways, and production of secondary metabolites. These metabolic adaptations might play a crucial role in biofilm formation by Gram-positive pathogens such as Staphylococcus aureus and Enterococcus faecalis. Here, we performed a transcriptomic approach to identify cellular pathways that might be similarly regulated during biofilm formation in these bacteria. Different strains and biofilm-inducing media were used to identify a set of regulated genes that are common and independent of the environment or accessory genomes analyzed. Our approach highlighted that the de novo purine biosynthesis pathway was upregulated in biofilms of both species when using a tryptone soy broth-based medium but not so when a brain heart infusion-based medium was used. We did not identify other pathways commonly regulated between both pathogens. Gene deletions and usage of a drug targeting a key enzyme showed the importance of this pathway in biofilm formation of S. aureus. The importance of the de novo purine biosynthesis pathway might reflect an important need for purine during biofilm establishment, and thus could constitute a promising drug target. IMPORTANCE Biofilms are often involved in nosocomial infections and can cause serious chronic infections if not treated properly. Current anti-biofilm strategies rely on antibiotic usage, but they have a limited impact because of the biofilm intrinsic tolerance to drugs. Metabolism remodeling likely plays a central role during biofilm formation. Using comparative transcriptomics of different strains of Staphylococcus aureus and Enterococcus faecalis, we determined that almost all cellular adaptations are not shared between strains and species. Interestingly, we observed that the de novo purine biosynthesis pathway was upregulated during biofilm formation by both species in a specific medium. The requirement for purine could constitute an interesting new anti-biofilm target with a wide spectrum that could also prevent resistance evolution. These results are also relevant to a better understanding of the physiology of biofilm formation.

Molecular modeling studies of pseudouridine isoxazolidinyl nucleoside analogues as potential inhibitors of the pseudouridine 5ʹ-monophosphate glycosidase

2017 ◽  
Vol 91 (2) ◽  
pp. 519-525 ◽  
Author(s):  
Giuseppe Floresta ◽  
Venerando Pistarà ◽  
Emanuele Amata ◽  
Maria Dichiara ◽  
Arcangelo Damigella ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Nucleoside Analogues ◽  
Modeling Studies ◽  
Molecular Modeling Studies ◽  
Potential Inhibitors

scholarly journals Potential inhibitors of SARS CoV-2 from Neocarya macrophylla: Chemoinformatic and Molecular modeling studies against three key targets

2021 ◽  
Vol 0 (0) ◽  
pp. 0-0
Author(s):  
Amina Jega YUSUF ◽  
Musa Ismail ABDULLAHI ◽  
Aliyu Muhammad MUSA ◽  
Hassan ABUBAKAR ◽  
Abubakar Muhammad AMALI ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Modeling Studies ◽  
Molecular Modeling Studies ◽  
Potential Inhibitors

Bisindolylmethane thiosemicarbazides as potential inhibitors of urease: Synthesis and molecular modeling studies

2018 ◽  
Vol 26 (1) ◽  
pp. 152-160 ◽  
Author(s):  
Muhammad Taha ◽  
Hayat Ullah ◽  
Laode Muhammad Ramadhan Al Muqarrabun ◽  
Muhammad Naseem Khan ◽  
Fazal Rahim ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Modeling Studies ◽  
Molecular Modeling Studies ◽  
Potential Inhibitors

p-Trifluoroacetophenone Oxime Ester Derivatives: Synthesis, Antimicrobial and Cytotoxic Evaluation and Molecular Modeling Studies

2020 ◽  
Vol 17 (2) ◽  
pp. 169-183 ◽  
Author(s):  
İrem Bozbey ◽  
Suat Sari ◽  
Emine Şalva ◽  
Didem Kart ◽  
Arzu Karakurt
Keyword(s):  
Molecular Modeling ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Cytotoxic Agents ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Modeling Studies ◽  
Broth Microdilution Method ◽  
Molecular Modeling Studies

Background: Azole antifungals are among the first-line drugs clinically used for the treatment of systemic candidiasis, a deadly type of fungal infection that threatens mostly immunecompromised and hospitalized patients. Some azole derivatives were also reported to have antiproliferative effects on cancer cells. Objective: In this study, 1-(4-trifluoromethylphenyl)-2-(1H-imidazol-1-yl)ethanone (3), its oxime (4), and a series of its novel oxime ester derivatives (5a-v) were synthesized and tested for their in vitro antimicrobial activities against certain ATCC standard strains of Candida sp. fungi and bacteria. The compounds were also tested for their cytotoxic effects against mouse fibroblast and human neuroblastoma cell lines. Molecular modeling studies were performed to provide insights into their possible mechanisms for antifungal and antibacterial actions. Methods: The compounds were synthesized by the reaction of various oximes with acyl chlorides. Antimicrobial activity of the compounds was determined according to the broth microdilution method. For the determination of cytotoxic effect, we used MTS assay. Molecular docking and QM/MM studies were performed to predict the binding mechanisms of the active compounds in the catalytic site of C. albicans CYP51 (CACYP51) and S. aureus flavohemoglobin (SAFH), the latter of which was created via homology modeling. Results: 5d, 5l, and 5t showed moderate antifungal activity against C. albicans, while 3, 5c, and 5r showed significant antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. Most of the compounds showed approximately 40-50% inhibition against the human neuroblastoma cells at 100 µM. In this line, 3 was the most potent with an IC50 value of 82.18 μM followed by 5a, 5o, and 5t. 3 and 5a were highly selective to the neuroblastoma cells. Molecular modelling results supported the hypothesis that our compounds were inhibitors of CAYP51 and SAFH. Conclusion: This study supports that oxime ester derivatives may be used for the development of new antimicrobial and cytotoxic agents.

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