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51.
Mohammad Hassan Baig Tanuj Sharma Irfan Ahmad Mohammed Abohashrh Mohammad Mahtab Alam Jae-June Dong 《Molecules (Basel, Switzerland)》2021,26(6)
The COVID-19 outbreak continues to spread worldwide at a rapid rate. Currently, the absence of any effective antiviral treatment is the major concern for the global population. The reports of the occurrence of various point mutations within the important therapeutic target protein of SARS-CoV-2 has elevated the problem. The SARS-CoV-2 main protease (Mpro) is a major therapeutic target for new antiviral designs. In this study, the efficacy of PF-00835231 was investigated (a Mpro inhibitor under clinical trials) against the Mpro and their reported mutants. Various in silico approaches were used to investigate and compare the efficacy of PF-00835231 and five drugs previously documented to inhibit the Mpro. Our study shows that PF-00835231 is not only effective against the wild type but demonstrates a high affinity against the studied mutants as well. 相似文献
52.
Kamel Arraki Perle Totoson Alain Decendit Andy Zedet Justine Maroilley Alain Badoc Cline Demougeot Corine Girard 《Molecules (Basel, Switzerland)》2021,26(6)
Polyphenolic enriched extracts from two species of Cyperus, Cyperus glomeratus and Cyperus thunbergii, possess mammalian arginase inhibitory capacities, with the percentage inhibition ranging from 80% to 95% at 100 µg/mL and 40% to 64% at 10 µg/mL. Phytochemical investigation of these species led to the isolation and identification of two new natural stilbene oligomers named thunbergin A-B (1–2), together with three other stilbenes, trans-resveratrol (3), trans-scirpusin A (4), trans-cyperusphenol A (6), and two flavonoids, aureusidin (5) and luteolin (7), which were isolated for the first time from C. thunbergii and C. glomeratus. Structures were established on the basis of the spectroscopic data from MS and NMR experiments. The arginase inhibitory activity of compounds 1–7 was evaluated through an in vitro arginase inhibitory assay using purified liver bovine arginase. As a result, five compounds (1, 4–7) showed significant inhibition of arginase, with IC50 values between 17.6 and 60.6 µM, in the range of those of the natural arginase inhibitor piceatannol (12.6 µM). In addition, methanolic extract from Cyperus thunbergii exhibited an endothelium and NO-dependent vasorelaxant effect on thoracic aortic rings from rats and improved endothelial dysfunction in an adjuvant-induced arthritis rat model. 相似文献
53.
Yasir Nazir Hummera Rafique Naghmana Kausar Qamar Abbas Zaman Ashraf Pornchai Rachtanapun Kittisak Jantanasakulwong Warintorn Ruksiriwanich 《Molecules (Basel, Switzerland)》2021,26(9)
Targeting tyrosinase for melanogenesis disorders is an established strategy. Hydroxyl-substituted benzoic and cinnamic acid scaffolds were incorporated into new chemotypes that displayed in vitro inhibitory effects against mushroom and human tyrosinase for the purpose of identifying anti-melanogenic ingredients. The most active compound 2-((4-methoxyphenethyl)amino)-2-oxoethyl (E)-3-(2,4-dihydroxyphenyl) acrylate (Ph9), inhibited mushroom tyrosinase with an IC50 of 0.059 nM, while 2-((4-methoxyphenethyl)amino)-2-oxoethyl cinnamate (Ph6) had an IC50 of 2.1 nM compared to the positive control, kojic acid IC50 16700 nM. Results of human tyrosinase inhibitory activity in A375 human melanoma cells showed that compound (Ph9) and Ph6 exhibited 94.6% and 92.2% inhibitory activity respectively while the positive control kojic acid showed 72.9% inhibition. Enzyme kinetics reflected a mixed type of inhibition for inhibitor Ph9 (Ki 0.093 nM) and non-competitive inhibition for Ph6 (Ki 2.3 nM) revealed from Lineweaver–Burk plots. In silico docking studies with mushroom tyrosinase (PDB ID:2Y9X) predicted possible binding modes in the catalytic site for these active compounds. Ph9 displayed no PAINS (pan-assay interference compounds) alerts. Our results showed that compound Ph9 is a potential candidate for further development of tyrosinase inhibitors. 相似文献
54.
Type 2 diabetes mellitus (T2DM) is one of the most widely prevalent metabolic disorders with no cure to date thus remains the most challenging task in the current drug discovery. Therefore, the only strategy to control diabetes prevalence is to develop novel efficacious therapeutics. Dipeptidyl Peptidase 4 (DPP-4) inhibitors are currently used as anti-diabetic drugs for the inhibition of incretins. This study aims to construct the chemical feature based on pharmacophore models for dipeptidyl peptidase IV. The structure-based pharmacophore modeling has been employed to evaluate new inhibitors of DPP-4. A four-featured pharmacophore model was developed from crystal structure of DPP-4 enzyme with 4-(2-aminoethyl) benzenesulfonyl fluoride in its active site via pharmacophore constructing tool of Molecular Operating Environment (MOE) consisting F1 Hyd (hydrophobic region), F2 Hyd|Cat|Don (hydrophobic cationic and donor region), F3 Acc (acceptor region) and F4 Hyd (hydrophobic region). The generated pharmacophore model was used for virtual screening of in-house compound library (the available compounds which were used for initial screening to get the few compounds for the current studies). The resultant selected compounds, after virtual screening were further validated using in vitro assay. Furthermore, structure-activity relationship was carried out for the compounds possessing significant inhibition potential after docking studies. The binding free energy of analogs was evaluated via molecular mechanics generalized Born surface area (MM-GBSA) and Poisson-Boltzmann surface area (MM-PBSA) methods using AMBER 16 as a molecular dynamics (MD) simulation package. Based on potential findings, we report that selected candidates are more likely to be used as DPP-4 inhibitors or as starting leads for the development of novel and potent DPP-4 inhibitors. 相似文献
55.
Bumhee Lim Yangyang Cheng Takehiro Kato Anh-Tuan Pham Eliott Le Du Abhaya Kumar Mishra Elija Grinhagena Dimitri Moreau Naomi Sakai Jerome Waser Stefan Matile 《Helvetica chimica acta》2021,104(8):e2100085
Thiol-mediated uptake is emerging as method of choice to penetrate cells. This study focuses on irreversible covalent inhibitors of thiol-mediated uptake. High-content high-throughput screening of the so far largest collection of hypervalent iodine reagents affords inhibitors that are more than 250 times more active than Ellman’s reagent and rival the best dynamic covalent inhibitors. Comparison with other irreversible reagents reveals that inhibition within one series follows reactivity, whereas inhibition across series deviates from reactivity. These trends support that molecular recognition, besides dynamic covalent exchange, contributes significantly to thiol-mediated uptake. The most powerful inhibitors besides the best hypervalent iodine reagents were Fukuyama’s nosyl protecting group and super-cinnamaldehydes that have been introduced as irreversible activators of the pain receptor TRPA1. Considering that several viruses use different forms of thiol-mediated uptake to enter cells, the identification of new irreversible inhibitors of thiol-mediated uptake is of general interest for the discovery of new antivirals. 相似文献
56.
The spectroscopic properties of Nω-nitro-l-arginine were investigated by FT-IR, UV-VIS, and 1H NMR spectra. Geometrical parameters and energies were calculated using the density functional theory (DFT) B3LYP method with the 6-311G basis set. Geometrical optimization of the molecule has been performed, vibrational spectra have been calculated, and fundamental vibrations have been determined from the total energy distribution (TED) of the vibrational modes. The HOMO-LUMO analysis is carried out for various electric fields (0.0–0.025 A?1). The HOMO-LUMO gap is decreased while increasing the electric field. The calculated quantum chemical parameters are calculated and correlated to the inhibition efficiency, A Mullliken population was also important for determining local reactivity by indicating reactive centers and identifying potential nucleophilic and electrophilic attack sites. Charge transfer occurs inside the compound based on the HOMO LUMO gap. Calculations of DFT were evaluated in their ability to predict inhibition efficiency. 相似文献
57.
Dr. Santiago Alonso-Gil Dr. Kamil Parkan Dr. Jakub Kaminský Dr. Radek Pohl Dr. Takatsugu Miyazaki 《Chemistry (Weinheim an der Bergstrasse, Germany)》2022,28(14):e202200148
The conformational changes in a sugar moiety along the hydrolytic pathway are key to understand the mechanism of glycoside hydrolases (GHs) and to design new inhibitors. The two predominant itineraries for mannosidases go via OS2→B2,5→1S5 and 3S1→3H4→1C4. For the CAZy family 92, the conformational itinerary was unknown. Published complexes of Bacteroides thetaiotaomicron GH92 catalyst with a S-glycoside and mannoimidazole indicate a 4C1→4H5/1S5→1S5 mechanism. However, as observed with the GH125 family, S-glycosides may not act always as good mimics of GH's natural substrate. Here we present a cooperative study between computations and experiments where our results predict the E5→B2,5/1S5→1S5 pathway for GH92 enzymes. Furthermore, we demonstrate the Michaelis complex mimicry of a new kind of C-disaccharides, whose biochemical applicability was still a chimera. 相似文献
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60.
Agnethe Knudsen Odile Diou Johan Sjöblom 《Journal of Dispersion Science and Technology》2013,34(10):1514-1524
Precipitation of naphthenate salts is normally a problem in the processing of acidic crude oils. In this study, the goal was to find suitable methods to investigate the interfacial reaction between tetraacid and calcium under emulsified conditions. Two different systems have been studied depending on composition and applied shear. The influence of inhibitors has been investigated and the same inhibitor was found to be the most effective one regardless of the system. Depletion of tetraacid in the oil phase was analyzed with UV-vis and HPLC. Interfacial area and droplet size in the emulsions were measured with fluorescence microscope and pulse-field gradient NMR. Since this reaction takes place over the interface, the investigation clearly documents, the importance of the total interfacial area of the emulsified system. 相似文献