inhibition constants
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Author(s):  
Katrina L Forrestall ◽  
Darcy E Burley ◽  
Meghan Kirsten Cash ◽  
Ian Pottie ◽  
Sultan Darvesh

COVID-19, caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2) currently has no treatment for acute infection. The main protease (Mpro) of SARS-CoV-2 is an essential enzyme for viral replication and an attractive target for disease intervention. The phenothiazine moiety has demonstrated drug versatility for biological systems, including inhibition of butyrylcholinesterase, a property important in the cholinesterase anti-inflammatory cascade. Nineteen phenothiazine drugs were investigated using in silico modelling techniques to predict binding energies and inhibition constants (Ki values) with SARS-CoV-2 Mpro. Since most side-effects of phenothiazines are due to interactions with various neurotransmitter receptors and transporters, phenothiazines with few such interactions were also investigated. All compounds were found to bind to the active site of SARS-CoV-2 Mpro and showed Ki values ranging from 1.30 to 52.4 µM. Nine phenothiazines showed inhibition constants <10 µM. The compounds with limited interactions with neurotransmitter receptors and transporters showed micromolar (µM) Ki values. Docking results were compared with remdesivir and showed similar interactions with key residues Glu-166 and Gln-189 in the active site. This work has identified several phenothiazines with limited neurotransmitter receptor and transporter interactions and that may provide the dual action of inhibiting SARS-CoV-2 Mpro to prevent viral replication and promote the release of anti-inflammatory cytokines to curb viral-induced inflammation. These compounds are promising candidates for further investigation against SARS-CoV-2.


2021 ◽  
Author(s):  
Yunzhuo Zhou ◽  
Raghad Al-Jarf ◽  
Azadeh Alavi ◽  
Thanh Binh Nguyen ◽  
Carlos H. M. Rodrigues ◽  
...  

Abstract Protein phosphorylation acts as an essential on/off switch in many cellular signalling pathways, regulating protein function. This has led to ongoing interest in targeting kinases for therapeutic intervention. Computer-aided drug discovery has been proven a useful and cost-effective approach for facilitating prioritisation and enrichment of screening libraries. Limited effort, however, has been devoted to developing and tailoring in silico tools to assist the development of kinase inhibitors and providing relevant insights on what makes potent inhibitors. To fill this gap, here we developed kinCSM, an integrative computational tool capable of accurately identifying potent cyclin-dependent kinase 2 (CDK2) inhibitors, quantitatively predicting CDK2 ligand-kinase inhibition constants (pKi) and classify inhibition modes without kinase information. kinCSM predictive models were built using supervised learning and leveraged the concept of graph-based signatures to capture both physicochemical properties and geometry properties of small molecules. CDK2 inhibitors were accurately identified with Matthew’s Correlation Coefficients of up to 0.74, and inhibition constants predicted with Pearson’s correlation of up to 0.76, both with consistent performances of 0.66 and 0.68 on non-redundant blind tests, respectively. kinCSM was also able to identify the potential type of inhibition for a given molecule, achieving Matthew’s Correlation Coefficient of up to 0.80 on cross-validation and 0.73 on blind test. Analysing the molecular composition of kinase inhibitors revealed enriched chemical fragments in potent CDK2 inhibitors and different types of inhibitors, which provides insights into the molecular mechanisms behind ligand-kinase interactions. We believe kinCSM will be an invaluable tool to guide future kinase drug discovery. To aid the fast and accurate screening of potent CDK2 kinase inhibitors, we made kinCSM freely available online at http://biosig.unimelb.edu.au/kin_csm/.


2021 ◽  

<p>Conversion of ammonia to nitrate is sensitive to a number of inhibitors. There is limited information on the nitrification inhibition coefficient and kinetic model in the current literature. Octyl Phenol Ethoxylate (OPE) and Bisphenol A (BPA) inhibition constants were found in nitrogen removal using an activated sludge system. Firstly, OPE and BPA free wastewater was used to determine the optimum operating conditions. The effect of OPE and BPA concentration on system performance was investigated. The ammonium removal rate was less affected by lower OPE and BPA concentrations. When the BPA and OPE concentrations were increased from 0 mg/L to 30 mg/L, the outlet ammonium nitrogen concentrations were increased respectively from 2.8 mg/L to 49.8 mg/L and from 2.6 mg/L to 20.40 mg/L. Due to the inhibition created by these compounds on Nitrobacter, nitrite nitrogen increased in the medium. As the OPE and BPA concentrations increased, the conversion rate of the ammonium nitrogen into nitrate decreased. Based on the experimental results, a kinetic model was developed, and the OPE and BPA inhibition constants (KOPE and KBPA) were found to be 40.7 mg/L and 11.76 mg/L, respectively. In nitrogen removal, BPA created a higher inhibition effect in comparison to OPE.</p>


Metabolites ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 136 ◽  
Author(s):  
Kesari Lakshmi Manasa ◽  
Sravya Pujitha ◽  
Aaftaab Sethi ◽  
Mohammed Arifuddin ◽  
Mallika Alvala ◽  
...  

A novel series of imidazo[2,1-b]thiazole-sulfonyl piperazine conjugates (9aa-ee) has been synthesized and evaluated for carbonic anhydrase (CA, EC 4.2.1.1) inhibitory potency against four isoforms: The cytosolic isozyme hCA I, II and trans-membrane tumor-associated isoform hCA IX and hCA XII, taking acetazolamide (AAZ) as standard drug, using a stopped flow CO2 hydrase assay. The results revealed that most of the compounds showed selective activity against hCA II whereas none of them were active against hCA I, IX, XII (Ki > 100 µM). The physiologically dominant cytosolic isoform hCA II was inhibited by these molecules with inhibition constants in the range of 57.7–98.2 µM. This new derivative, thus, selectively inhibits hCA II over the hCA I, IX, XII isoforms, which may be used for further understanding the physiological roles of some of these isoforms in various pathologies.


2020 ◽  
Vol 26 (7) ◽  
pp. 790-800
Author(s):  
Qazi M.S. Jamal ◽  
Mughees U. Siddiqui ◽  
Ali H. Alharbi ◽  
Fahad Albejaidi ◽  
Salman Akhtar ◽  
...  

: Keeping in view the public health-related issues of Alzheimer's disease (AD), its unpredictable occurrence and progression indicate the needs for best treatment options. The present bioinformatics study explores the binding pattern and molecular interactions between human acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes with natural compounds from Bacopa monnieri. The docking analysis between natural compounds as a ligand and AChE, BuChE as a receptor was completed using MGL tools Autodock 4.2 module. The analysis of the hydrophobic interactions, inhibition constants, and hydrogen bonds may indicates that they play a significant role in finding out the interacting position at the active site. However, after analyzing the binding energy (ΔG), the documented data shows that bacoside X, bacoside A, 3-beta-D-glucosylstigmasterol and daucosterol could be good inhibitors in the inhibition of AChE and BuChE activities. Therefore, our study indicates that the inhibition constants of the aforesaid natural compounds of Bacopa can be utilized for the development of inhibitors.


Nanoscale ◽  
2020 ◽  
Vol 12 (25) ◽  
pp. 13719-13730
Author(s):  
Tooba Hallaj ◽  
Mohammad Amjadi ◽  
Xue Qiu ◽  
Kimihiro Susumu ◽  
Igor L. Medintz ◽  
...  

Terbium-to-quantum dot FRET assays for quantifying SET7/9 methyltransferase at low picomolar concentrations, inhibition constants, and enzyme kinetics.


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