competitive inhibitor
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Processes ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 166
Geum-Seok Jeong ◽  
Eun-Young Lee ◽  
Myung-Gyun Kang ◽  
Sang-Jip Nam ◽  
Daeui Park ◽  

In this study, the inhibitory activities against human monoamine oxidases (hMAOs) were evaluated using a library of 195 endogenous lichen fungi from Ukraine. Among them, the extract ELF68 of the endogenous fungus Rosellinia corticium from the lichen Pseudevernia furfuracea (L.) Zopf. exhibited the strongest inhibitory activity against hMAO-A. Using the activity-guided method, (S)-5-methylmellein (5MM) was isolated from the extract and had an IC50 value of 5.31 µM for hMAO-A with a lower potency for hMAO-B (IC50 = 9.15 µM). Compound 5MM also moderately inhibited acetylcholinesterase (IC50 = 27.07 µM) but very weakly inhibited butyrylcholinesterase and β-secretase. Compound 5MM had a Ki value of 2.45 μM and was a reversible competitive inhibitor of hMAO-A. A molecular docking study predicted that (S)-5MM showed higher binding affinity for hMAO-A (−6.8 kcal/mol) than hMAO-B (−6.4 kcal/mol). Its isomer, (R)-5MM, exhibited lower binding affinities for hMAO-A (−6.6 kcal/mol) and hMAO-B (−5.2 kcal/mol), compared to (S)-5MM. The S-form interacted with hMAO-A through hydrogen bonding with the Phe208 residue (distance: 1.972 Å), while the R-form interacted with the Asn181 residue (2.375 Å). The results of an in silico pharmacokinetic analysis indicated that 5MM did not violate Lipinski’s five rules and showed high gastrointestinal absorption and blood–brain barrier permeability. These results suggest that 5MM can be considered a candidate in the treatment of neuropsychiatric disorders, such as depression and cardiovascular disease.

2022 ◽  
Vol 12 (1) ◽  
Milena do Amaral ◽  
Ana Camila Oliveira Freitas ◽  
Ariana Silva Santos ◽  
Everton Cruz dos Santos ◽  
Monaliza Macêdo Ferreira ◽  

AbstractProtease inhibitors (PIs) are important biotechnological tools of interest in agriculture. Usually they are the first proteins to be activated in plant-induced resistance against pathogens. Therefore, the aim of this study was to characterize a Theobroma cacao trypsin inhibitor called TcTI. The ORF has 740 bp encoding a protein with 219 amino acids, molecular weight of approximately 23 kDa. rTcTI was expressed in the soluble fraction of Escherichia coli strain Rosetta [DE3]. The purified His-Tag rTcTI showed inhibitory activity against commercial porcine trypsin. The kinetic model demonstrated that rTcTI is a competitive inhibitor, with a Ki value of 4.08 × 10–7 mol L−1. The thermostability analysis of rTcTI showed that 100% inhibitory activity was retained up to 60 °C and that at 70–80 °C, inhibitory activity remained above 50%. Circular dichroism analysis indicated that the protein is rich in loop structures and β-conformations. Furthermore, in vivo assays against Helicoverpa armigera larvae were also performed with rTcTI in 0.1 mg mL−1 spray solutions on leaf surfaces, which reduced larval growth by 70% compared to the control treatment. Trials with cocoa plants infected with Mp showed a greater accumulation of TcTI in resistant varieties of T. cacao, so this regulation may be associated with different isoforms of TcTI. This inhibitor has biochemical characteristics suitable for biotechnological applications as well as in resistance studies of T. cacao and other crops.

2022 ◽  
Kelly T. Rios ◽  
Taylor M. Dickson ◽  
Scott E Lindner

Some early antimalarial drugs have been repurposed for experimental applications, thus extending their utility well beyond the point when resistance becomes prevalent in circulating parasite populations. One such drug is sulfadiazine, which is an analog of p-aminobenzoic acid (pABA), and acts as a competitive inhibitor of dihydropteroate synthase, which is an essential enzyme in the parasite's folate synthesis pathway that is required for DNA synthesis. Sulfadiazine treatment of mice infected with P. yoelii and P. berghei is routinely used to enrich for gametocytes by killing asexual blood stage parasites, but it is not well known if the exposed gametocytes are perturbed or if there is a detrimental effect on transmission. To determine if there was a significant effect of sulfadiazine exposure upon host-to-vector transmission, we transmitted Plasmodium yoelii (17XNL strain) parasites to Anopheles stephensi mosquitoes and evaluated the prevalence of infection (percent of mosquitoes infected) and intensity of infection (number of oocysts per infected mosquito) under different sulfadiazine treatment conditions of the mouse or of the mosquitoes. We observed that parasites exposed to sulfadiazine either in the mouse host or in the mosquito vector had a reduction in both the number of mosquitoes that became infected and in the intensity of infection compared to untreated controls. We also observed that provision of freshly prepared pABA in the mosquito sugar water could only marginally overcome the defects caused by sulfadiazine treatment. In contrast, we determined that gametocytes exposed to sulfadiazine were able to be fertilized and develop into morphologically mature ookinetes in vitro, and thus that sulfadiazine exposure in the host may be reversible if the drug is washed out and the parasites are supplemented with pABA in the culture media. Overall, this indicates that sulfadiazine dampens host-to-vector transmission, and that this inhibition can only be partially overcome by exposure to fresh pABA in vivo and in vitro. Because gametocytes are of great interest for developing transmission blocking interventions, we recommend that less disruptive approaches for gametocyte enrichment be used in order to study minimally perturbed parasites.

Mahmoud N. M. Yousif ◽  
Abdel-Rahman B. A. El-Gazzar ◽  
Hend N. Hafez ◽  
Ahmed A. Fayed ◽  
Ahmed ElRashedy ◽  

Abstract: This review describes different synthetic methods for the preparation of sulfonamides. Generally, sulfonamides are synthesized from sulfonyl chloride derivative and amino derivative. A series of sulfonamide derivatives 7a-c, 8a,b, 9, 10, 11a,b, 12 were synthesized in alkaline media by reaction of different amino compounds with p-toluene sulfonyl chloride. Different amino derivatives 13, 15, 17, 19, 21 react with p-tolyl sulphonylchloride to afford sulfonylamides 14, 16, 18, 20, 22. Different reactions of sulfonamide derivatives have been summarized. Generally, sulfonamide function group does not take part in any reactions, but there are other functional groups in the compound which make the reactions. Sulfonamides have different biological activities e.g. antibacterial activity, anticancer activity, urease inhibitory activity, radical scavenging activity, carbonic anhydrase inhibitor, non-competitive inhibitor of lactoperoxidase, antifungal activity, and anti-mycobacterial activity.

Soraia R. Mendes ◽  
Ulrich Eckhard ◽  
Arturo Rodríguez-Banqueri ◽  
Tibisay Guevara ◽  
Peter Czermak ◽  

Kamalpreet Kaur ◽  
Taranjit Kaur ◽  
Ajeet Pal Singh ◽  
Amar Pal Singh

The improvement of a pure drug's solubility and dissolution rate in the treatment of hyperlipidemia. Simvastatin is a 5-percent absolute bioavailability selective competitive inhibitor of HMG Co-A reductase. For the selection of the carrier, a preliminary solubility investigation of solid dispersion was performed, and solid dispersion was made using Hydroxy Propyl Methyl Cellulose (HPMC) and gum acacia. Solid dispersion of medication with polymer was created and studied for solubility and in-vitro dissolution profile. Solid dispersion of drug with polymer has shown an increase in solubility and improved dissolution rate. On the obtained formulations, further FTIR, X-Ray, Scanning electron microscopy, and Differential scanning calorimetry experiments were conducted. The existence of amorphous form in a solid dispersion made with polymer in a 1:5 ratio is verified by characterization research. The research also showed that using a solid dispersion approach with Polymer, the dissolving rate of a pure medication may be significantly increased.

2021 ◽  
Vol 15 (1) ◽  
pp. 21
Otávio Augusto Chaves ◽  
Carolina Q. Sacramento ◽  
André C. Ferreira ◽  
Mayara Mattos ◽  
Natalia Fintelman-Rodrigues ◽  

Atazanavir (ATV) has already been considered as a potential repurposing drug to 2019 coronavirus disease (COVID-19); however, there are controversial reports on its mechanism of action and effectiveness as anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through the pre-clinical chain of experiments: enzymatic, molecular docking, cell-based and in vivo assays, it is demonstrated here that both SARS-CoV-2 B.1 lineage and variant of concern gamma are susceptible to this antiretroviral. Enzymatic assays and molecular docking calculations showed that SARS-CoV-2 main protease (Mpro) was inhibited by ATV, with Morrison’s inhibitory constant (Ki) 1.5-fold higher than GC376 (a positive control) dependent of the catalytic water (H2Ocat) content. ATV was a competitive inhibitor, increasing the Mpro’s Michaelis–Menten (Km) more than sixfold. Cell-based assays indicated that different lineages of SARS-CoV-2 is susceptible to ATV. Using oral administration of ATV in mice to reach plasmatic exposure similar to humans, transgenic mice expression in human angiotensin converting enzyme 2 (K18-hACE2) were partially protected against lethal challenge with SARS-CoV-2 gamma. Moreover, less cell death and inflammation were observed in the lung from infected and treated mice. Our studies may contribute to a better comprehension of the Mpro/ATV interaction, which could pave the way to the development of specific inhibitors of this viral protease.

2021 ◽  
Vol 5 (4) ◽  
pp. 347-352
Taufik Muhammad Fakih ◽  
Mentari Luthfika Dewi

The recent public health crisis is threatening the world with the emergence of the spread of the new coronavirus 2019 (2019-nCoV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus originates from bats and is transmitted to humans through unknown intermediate animals in Wuhan, China in December 2019. Advances in technology have opened opportunities to find candidates for natural compounds capable of preventing and controlling COVID-19 infection through inhibition of spike proteins of SARS-CoV-2. This research aims to identify, evaluate, and explore the structure of spike protein macromolecules from three coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2) and their effects on Angiotensin-Converting Enzyme 2 (ACE-2) using computational studies. Based on the identification of the three spike protein macromolecules, it was found that there was a similarity between the active binding sites of ACE-2. These observations were then confirmed using a protein-docking simulation to observe the interaction of the protein spike to the active site of ACE-2. SARS-COV-2 spike protein has the strongest bond to ACE-2, with an ACE score of −1341.85 kJ/mol. Therefore, some of this information from the results of this research can be used as a reference in the development of competitive inhibitor candidates for SARS-CoV-2 spike proteins for the treatment of COVID-19 infectious diseases.

2021 ◽  
Vol 22 (24) ◽  
pp. 13337
Sylwia Gul-Hinc ◽  
Anna Michno ◽  
Marlena Zyśk ◽  
Andrzej Szutowicz ◽  
Agnieszka Jankowska-Kulawy ◽  

Brain pathologies evoked by thiamine deficiency can be aggravated by mild zinc excess. Cholinergic neurons are the most susceptible to such cytotoxic signals. Sub-toxic zinc excess aggravates the injury of neuronal SN56 cholinergic cells under mild thiamine deficiency. The excessive cell loss is caused by Zn interference with acetyl-CoA metabolism. The aim of this work was to investigate whether and how astroglial C6 cells alleviated the neurotoxicity of Zn to cultured SN56 cells in thiamine-deficient media. Low Zn concentrations did not affect astroglial C6 and primary glial cell viability in thiamine-deficient conditions. Additionally, parameters of energy metabolism were not significantly changed. Amprolium (a competitive inhibitor of thiamine uptake) augmented thiamine pyrophosphate deficits in cells, while co-treatment with Zn enhanced the toxic effect on acetyl-CoA metabolism. SN56 cholinergic neuronal cells were more susceptible to these combined insults than C6 and primary glial cells, which affected pyruvate dehydrogenase activity and the acetyl-CoA level. A co-culture of SN56 neurons with astroglial cells in thiamine-deficient medium eliminated Zn-evoked neuronal loss. These data indicate that astroglial cells protect neurons against Zn and thiamine deficiency neurotoxicity by preserving the acetyl-CoA level.

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