Osmolyte induced enhancement of expression and solubility of human dihydrofolate reductase: An in vivo study

Rashid, Naira; Thapliyal, Charu; Chaudhuri, Pratima

doi:10.1016/j.ijbiomac.2017.05.143

Cited by 13 publications

(6 citation statements)

References 31 publications

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“…Infrared spectra were recorded on a Schimadzu FT-IR Affinity-1 Spectrometer, Infrared spectrometer at cm −1 scale using KBr disc technique. 1 H NMR and 13 C NMR spectra were determined by using a Bruker High Performance Digital FT-NMR Spectrometer Avance III 400 MHz. Chemical shifts were expressed in δ (ppm) downfield from TMS as an internal standard.…”

Section: Methodsmentioning

confidence: 99%

“…5,11,12 Therefore, the suppression of DHFR enzyme results in an imbalance in the synthetic pathway of active thymidylate, causing the disruption of DNA replication, which in turn leads to cell death. 13 Lately, DHFR structures of organisms like Mtb have been disclosed. 6−10 So, the discovery of new molecules as DHFR inhibitors especially against Mtb is a promising goal in the treatment of tuberculosis.…”

Section: Introductionmentioning

confidence: 99%

“…13 C NMR (DMSO-d 6 ): δ 14.72, 17.91, 44.29, 59.48, 60.69, 111.20, 126.15, 127.37, 128.72, 130.79, 131.44, 133.75, 143.58, 151.79, 159.49, 162.23, 164.97. MS: m/z (%) 403 (M + , 23.81).…”

mentioning

confidence: 99%

“…13 C NMR (DMSO-d 6 ): δ 19.09, 44.06, 49.49, 59.80, 126.24, 126.46, 127.46, 128.96, 132.23, 132.92, 133.15, 142.56, 156.52, 175.99, 189.91. MS: m/z (%) 347 (M + , 40.47).…”

mentioning

confidence: 99%

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New Thiophenyl-pyrazolyl-thiazole Hybrids as DHFR Inhibitors: Design, Synthesis, Antimicrobial Evaluation, Molecular Modeling, and Biodistribution Studies

Dawood,

Sayed,

Tohamy

et al. 2023

ACS Omega

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The antibiotic resistance problems constitute a considerable threat to human health worldwide; thus, the discovery of new antimicrobial candidates to conquer this issue is an imperative requirement. From this view, new thiophenyl-pyrazolyl-thiazole hybrids 3–10 were synthesized and screened for their antibacterial efficiency versus Gram – and Gram + bacterial strains compared to the reference drug amoxicillin. It was noticed that the new hybrids displayed significant antibacterial efficacy versus Gram – bacteria, especially against Pseudomonas aeruginosa. Also, all the screened candidates demonstrated a noticeable antifungal effect against Candida albicans (MICs = 3.9–125 μg/mL) relative to fluconazole (MIC = 250 μg/mL). Moreover, the new hybrids were investigated for their antituberculosis potency against Mycobacterium tuberculosis (RCMB 010126). Derivatives 4c, 6b, 8b, 9b, and 10b demonstrated prominent antituberculosis efficiency (MICs = 0.12–1.95 μg/mL) compared with the reference drug isoniazid (MIC = 0.12 μg/mL). The latter derivatives were further assessed for their inhibitory potency versus M. tuberculosis DHFR enzyme. The compounds 4c, 6b and 10b presented a remarkable suppression effect with IC50 values of 4.21, 5.70, and 10.59 μM, respectively, compared to that of trimethoprim (IC50 = 6.23 μM). Furthermore, biodistribution profile using radiolabeling way revealed a perceived uptake of 131I-compound 6b into infection induced models. The docking study for the new hybrids 4c, 6b, 8b, 9b and 10b was performed to illustrate the various binding modes with Mtb DHFR enzyme. In silico ADMET studies for the most potent inhibitors 4c, 6b and 10b were also accomplished to predict their pharmacokinetic and physicochemical features.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…13 C NMR (DMSO-d 6 ): δ 14.72, 17.91, 44.29, 59.48, 60.69, 111.20, 126.15, 127.37, 128.72, 130.79, 131.44, 133.75, 143.58, 151.79, 159.49, 162.23, 164.97. MS: m/z (%) 403 (M + , 23.81).…”

mentioning

confidence: 99%

“…13 C NMR (DMSO-d 6 ): δ 19.09, 44.06, 49.49, 59.80, 126.24, 126.46, 127.46, 128.96, 132.23, 132.92, 133.15, 142.56, 156.52, 175.99, 189.91. MS: m/z (%) 347 (M + , 40.47).…”

mentioning

confidence: 99%

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New Thiophenyl-pyrazolyl-thiazole Hybrids as DHFR Inhibitors: Design, Synthesis, Antimicrobial Evaluation, Molecular Modeling, and Biodistribution Studies

Dawood,

Sayed,

Tohamy

et al. 2023

ACS Omega

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“…These biological substances can be further categorized into (i) osmolytes, such as trim ethylamine N-oxide (TMAO), sarcosine, sorbitol, sucrose and trehalose, that stabilize proteins by raising free energy of both native and denatured states, (ii) osmolytes, such as, glycine, betaine, proline and glycerol, that only moderately enhance the thermodynamic stability of proteins, (iii) denaturing osmolytes, such asurea, and (iv) counteracting osmolytes, such as the mixture of urea and TMAO) [5]. Over the last decades, an increasing number of studies have broadened the diverse functions of biological osmolytes pertaining to solubility of proteins [6][7][8][9][10], expression enhancement of enzymes [11,12], and protection of living organisms against extreme environmental conditions [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of Biological Osmolytes against Heat- and Chaotropic Agent-Induced Denaturation of Bacillus licheniformis ��-Glutamyl Transpeptidase

Chi

Lin

et al. 2018

Journal of Microbiology and Biotechnology

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In the present study, the stabilizing effect of four different biological osmolytes on Bacillus licheniformis γ-glutamyl transpeptidase (BlGGT) was investigated. BlGGT appeared to be stable under temperatures below 40°C, but the enzyme retained less than 10% of its activity at 60°C. The tested osmolytes exhibited different degrees of effectiveness against temperature inactivation of BlGGT, and sucrose was found to be the most effective among these. The use of circular dichroism spectroscopy for studying the secondary structure of BlGGT revealed that the temperature-induced conformational change of the protein molecule could be prevented by the osmolytes. Consistently, the molecular structure of the enzyme was essentially conserved by the osmolytes at elevated temperatures as monitored by fluorescence spectroscopy. Sucrose was further observed to counteract guanidine hydrochloride (GdnHCl)and urea-induced denaturation of BlGGT. Taken together, we observed evidently that some well-known biological osmolytes, especially sucrose, make a dominant contribution to the structural stabilization of BlGTT.

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Evolutionarily Related Dihydrofolate Reductases Perform Coequal Functions Yet Show Divergence in Their Trajectories

Rashid

Chattopadhyay

2018

Protein J

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The enzyme dihydrofolate reductase (DHFR) catalyzes NADPH dependent reduction of dihydrofolate to tetrahydrofolate. It plays a crucial role in the DNA synthesis. The investigation of evolution of DHFR generates immense curiosity. It aids in predicting how the enzyme has adapted to the surroundings of various cell types. In spite of great similarity in the structure of E. coli DHFR and human DHFR, their primary sequences are divergent to a great extent, which is evident in variations in the kinetics mechanism of their catalysis. In presence of physiological levels of ligands, they possess distinct kinetics and different rate limiting steps. We have reviewed the process of their unfolding and refolding, their behaviour in denaturing conditions and in presence of various chaperones. Although there is structural similarity between these two homologous enzymes yet they have established distinct mechanisms to accomplish the coequal functions.

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Osmolyte induced enhancement of expression and solubility of human dihydrofolate reductase: An in vivo study

Cited by 13 publications

References 31 publications

New Thiophenyl-pyrazolyl-thiazole Hybrids as DHFR Inhibitors: Design, Synthesis, Antimicrobial Evaluation, Molecular Modeling, and Biodistribution Studies

New Thiophenyl-pyrazolyl-thiazole Hybrids as DHFR Inhibitors: Design, Synthesis, Antimicrobial Evaluation, Molecular Modeling, and Biodistribution Studies

Protective Effect of Biological Osmolytes against Heat- and Chaotropic Agent-Induced Denaturation of Bacillus licheniformis ��-Glutamyl Transpeptidase

Evolutionarily Related Dihydrofolate Reductases Perform Coequal Functions Yet Show Divergence in Their Trajectories

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