qsar analysis
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Author(s):  
Kousuke Nishikiori ◽  
Kentaro Tanaka ◽  
Yoshihiro Uesawa

Abstract In designing drug dosing for hemodialysis patients, the removal rate (RR) of the drug by hemodialysis is important. However, acquiring the RR is difficult, and there is a need for an estimation method that can be used in clinical settings. In this study, the RR predictive model was constructed using the RR of known drugs by quantitative structure–activity relationship (QSAR) analysis. Drugs were divided into a model construction drug set (75%) and a model validation drug set (25%). The RR was collected from 143 medicines. The objective variable (RR) and chemical structural characteristics (descriptors) of the drug (explanatory variable) were used to construct a prediction model using partial least squares (PLS) regression and artificial neural network (ANN) analyses. The determination coefficients in the PLS and ANN methods were 0.586 and 0.721 for the model validation drug set, respectively. QSAR analysis successfully constructed dialysis RR prediction models that were comparable or superior to those using pharmacokinetic parameters. Considering that the RR dataset contains potential errors, we believe that this study has achieved the most reliable RR prediction accuracy currently available. These predictive RR models can be achieved using only the chemical structure of the drug. This model is expected to be applied at the time of hemodialysis. Graphic Abstract


2022 ◽  
Vol 1247 ◽  
pp. 131400
Author(s):  
Vishal K Singh ◽  
Himani Chaurasia ◽  
Richa Mishra ◽  
Ritika Srivastava ◽  
Farha Naaz ◽  
...  

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Alina Bărbulescu ◽  
Lucica Barbeș ◽  
Cristian-Ştefan Dumitriu

The appearance on the free market of synthetic cannabinoids raised the researchers’ interest in establishing their molecular similarity by QSAR analysis. A rigorous criterion for classifying drugs is their chemical structure. Therefore, this article presents the structural similarity of two groups of drugs: benzoylindoles and phenylacetylindoles. Statistical analysis and clustering of the molecules are performed based on their numerical characteristics extracted using Cheminformatics methods. Their similarities/dissimilarities are emphasized using the dendrograms and heat map. The highest discrepancies are found in the phenylacetylindoles group.


Author(s):  
Laxmi Banjare ◽  
Yogesh Singh ◽  
Sant Kumar Verma ◽  
Atul Kumar Singh ◽  
Pradeep Kumar ◽  
...  

2021 ◽  
Vol 5 (4) ◽  
Author(s):  
Svetlana Dekina

Background. The catalytic activity of enzymes, which is their most important characteristic, can change significantly under the influence of effectors, for example, metal ions, and is the subject of special studies that are important for biochemistry, biotechnology, medicine, and other branches of science. Usually, the activity of enzymes in the presence of metals is assessed by the change in the rate of the enzymatic reaction. However, conducting similar experimental studies, especially for new enzymes, as in the case of peptidase Bacillus thuringiensis var. israelensis IMV B-7465, requires significant resources and extensive kinetic research. Therefore, it is advisable to use the methods of computer chemistry, the basic task of which is to search for the structure-property relationship, to build a model that can, with a high degree of probability, assess the effect of metal ions on the activity of peptidase. Objective: Objective: to develop of QSAR models to analyze and prediction the effect of metal ions on the activity of peptidase Bacillus thuringiensis var. israelensis IMV B-7465. Methods: the effect of metal ions was studied by determining the proteolytic activity of peptidase after joint incubation for 30 min in 0.0167 M Tris-HCl buffer solution (pH 7.5, 37 ° C). Final concentration of metal chlorides Li +; Na +; K +; Cs +; Cu2 +; Be2 +; Mg2 +; Ca2 +; Sr2 +; Ba2 +; Zn2 +; Cd2 +; Hg2 +; Cr3 +; Mn2 +; Co2 +; Ni2 + in the buffer solution was 4 mmol / dm3. To search for the quantitative “structure-property” relationship we used the reference data on the properties of metal ions and trend vector and random forest methods. Results: the effect of metal ions on the proteolytic activity of peptidase Bacillus thuringiensis var. israelensis IMV B-7465, some metal ions (Li +, Mn2 +, and Co2 +) activated peptidase, while others (Cu2 +, Be2 +, Cd2 +, Hg2 +, Cr3 +) inhibited the enzyme activity. Adequate statistical models without classification errors and prediction errors for the test set were constructed by nonlinear methods of trend-vector and random forest. Both models show that the most important characteristics of metal ions that affect enzyme activity are electronegativity (ENPol), first ionization potential (IP1), the entropy of ions in aqueous solution (S) and the electron affinity energy (Eae). Conclusions: methods of QSAR analysis in combination with nonlinear methods of trend vector and random forest allow to adequately describe the influence of metal ions on the activity of peptidase Bacillus thuringiensis var. israelensis IMV B-7465 due to descriptors that reflect a certain balance of their electron-donor and electron-acceptor properties (electronegativity, first ionization potential, electron affinity energy) and the degree of the hydrate shell structurization (entropy of solvation). Both statistical methods give similar values of the importance of descriptors, but only the trend vector method allows to analyze the direction of influence of specific characteristics of ions.


2021 ◽  
Author(s):  
Melanie Voigt ◽  
Victoria Langerbein ◽  
Martin Jaeger

Abstract BackgroundImidacloprid is among the most widely used insecticides and today is found in surface and ground water worldwide. Together with four other neonicotinoids, it has been registered in the EU watchlist for monitoring. To prevent imidacloprid from entering water bodies, Advanced Oxidation Processes have been intensely researched. Photoirradiation proved one of the most efficient methods to degrade and eliminate anthropogenic micropollutants from waters. Their ecotoxicity assessment of photoinduced degradation and transformation products especially in the absence of reference standards is still heavily explored.ResultsIn this study, UVA and UVC irradiation in combination with titanium dioxide P25 as photocatalyst were investigated for their degrading and eliminating effects and effectiveness on imidacloprid. Humic acid was used as natural organic matter additive. High-performance liquid chromatography coupled with high-resolution and higher order mass spectrometry allowed to identify and monitor imidacloprid and its degradation intermediates yielding seven new structures and concentration-time (c-t) profiles. The correlation of structures and the application of radical scavengers and photocatalyst helped distinguish between direct photoinduced and indirect hydroxyl-radical induced degradation mechanisms. Only imidacloprid-urea and desnitro-imidacloprid resulted from direct degradation, all other products from the indirect mechanism. The ecotoxicity of all identified compounds was assessed by quantitative structure activity relationship (QSAR) analysis. Ecotoxicity equivalents (ETEs) were introduced allowing a classified ranking of the products and an assessment of the overall hazardous potential of the irradiated solution at a given moment. Generally, the number of hydroxyl substituents was inversely correlated to ecotoxicity due to a single product. From the c-t curves, time-dependent ETE profiles were established.ConclusionsStructure elucidation and c-t profiles from liquid chromatography-high resolution mass spectrometry allowed to distinguish between direct and indirect degradation mechanisms. Structure specific ecotoxicity assessment could be achieved through QSAR analysis. Ecotoxicity hazard was ranked based on ETEs. The time-dependent ETE profile proved suitable to reflect the effect of irradiation duration and allow to estimate the irradiation time required to eliminate ecotoxicity, which may be relevant for potential applications in wastewater treatment plants.


2021 ◽  
Vol 14 (12) ◽  
pp. 1296
Author(s):  
Roberto Sabbadini ◽  
Emanuela Pesce ◽  
Alice Parodi ◽  
Eleonora Mustorgi ◽  
Santina Bruzzone ◽  
...  

Cystic fibrosis (CF) is caused by different mutations related to the cystic fibrosis transmembrane regulator protein (CFTR), with F508del being the most common. Pioneering the development of CFTR modulators, thanks to the development of effective correctors or potentiators, more recent studies deeply encouraged the administration of triple combination therapeutics. However, combinations of molecules interacting with other proteins involved in functionality of the CFTR channel recently arose as a promising approach to address a large rescue of F508del-CFTR. In this context, the design of compounds properly targeting the molecular chaperone Hsp70, such as the allosteric inhibitor MKT-077, proved to be effective for the development of indirect CFTR modulators, endowed with ability to amplify the accumulation of the rescued protein. Herein we performed structure-based studies of a number of allosteric HSP70 inhibitors, considering the recent X-ray crystallographic structure of the human enzyme. This allowed us to point out the main interaction supporting the binding mode of MKT-077, as well as of the related analogues. In particular, cation-π and π–π stacking with the conserve residue Tyr175 deeply stabilized inhibitor binding at the HSP70 cavity. Molecular docking studies had been followed by QSAR analysis and then by virtual screening of aminoaryl thiazoles (I–IIIa) as putative HSP70 inhibitors. Their effectiveness as CFTR modulators has been verified by biological assays, in combination with VX-809, whose positive results confirmed the reliability of the whole applied computational method. Along with this, the “in-silico” prediction of absorption, distribution, metabolism, and excretion (ADME) properties highlighted, once more, that AATs may represent a chemical class to be further investigated for the rational design of novel combination of compounds for CF treatment.


Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6948
Author(s):  
Mei Huang ◽  
Wen-Gui Duan ◽  
Gui-Shan Lin ◽  
Bao-Yu Li

A series of novel menthol derivatives containing 1,2,4-triazole-thioether moiety were designed, synthesized, characterized structurally, and evaluated biologically to explore more potent natural product-based antifungal agents. The bioassay results revealed that at 50 μg/mL, some of the target compounds exhibited good inhibitory activity against the tested fungi, especially against Physalospora piricola. Compounds 5b (R = o-CH3 Ph), 5i (R = o-Cl Ph), 5v (R = m, p-OCH3 Ph) and 5x (R = α-furyl) had inhibition rates of 93.3%, 79.4%, and 79.4%, respectively, against P. piricola, much better than that of the positive control chlorothalonil. Compounds 5v (R = m, p-OCH3 Ph) and 5g (R = o-Cl Ph) held inhibition rates of 82.4% and 86.5% against Cercospora arachidicola and Gibberella zeae, respectively, much better than that of the commercial fungicide chlorothalonil. Compound 5b (R = o-CH3 Ph) displayed antifungal activity of 90.5% and 83.8%, respectively, against Colleterichum orbicalare and Fusarium oxysporum f. sp. cucumerinum. Compounds 5m (R = o-I Ph) had inhibition rates of 88.6%, 80.0%, and 88.0%, respectively, against F.oxysporum f. sp. cucumerinu, Bipolaris maydis and C. orbiculare. Furthermore, compound 5b (R = o-CH3 Ph) showed the best and broad-spectrum antifungal activity against all the tested fungi. To design more effective antifungal compounds against P. piricola, 3D-QSAR analysis was performed using the CoMFA method, and a reasonable 3D-QSAR model (r2 = 0.991, q2= 0.514) was established. The simulative binding pattern of the target compounds with cytochrome P450 14α-sterol demethylase (CYP51) was investigated by molecular docking.


Biology ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1145
Author(s):  
Yin Luo ◽  
Yushun Yang ◽  
Wenguang Hou ◽  
Jie Fu

Cyanobacteria bloom caused by water eutrophication has threatened human health and become a global environmental problem. To develop green algicides with strong specificity and high efficiency, three series of ester and amide derivatives from parent allelochemicals of caffeic acid (CA), cinnamic acid (CIA), and 3-hydroxyl-2-naphthoic acid (HNA) were designed and synthesized. Their inhibitory effects on the growth of five harmful cyanobacterial species, Microcystis aeruginosa (M. aeruginosa), Microcystis wesenbergii (M. wesenbergii), Microcystis flos-aquae (M. flos-aquae), Aphanizomenon flos-aquae (Ap. flos-aquae), and Anabaena flos-aquae (An. flos-aquae), were evaluated. The results revealed that CIA esters synthesized by cinnamic acid and fatty alcohols showed the best inhibition effect, with EC50 values ranging from 0.63 to >100 µM. Moreover, some CIA esters exhibited a good selectivity in inhibiting cyanobacteria. For example, the inhibitory activity of naphthalen-2-yl cinnamate was much stronger on Ap. flos-aquae (EC50 = 0.63 µM) than other species (EC50 > 10 µM). Three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis was performed and the results showed that the steric hindrance of the compounds influenced the algicidal activity. Further mechanism study found that the inhibition of CIA esters on the growth of M. aeruginosa might be related to the accumulation of malondialdehyde (MDA).


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