Molecular basis of structural stability of Irisin: A combined molecular dynamics simulation and in vitro studies for Urea-induced denaturation

Waseem, Rashid; Yadav, Neetu Singh; Khan, Tanzeel; Ahmad, Faizan; Kazim, Syed Naqui; Hassan, Imtaiyaz; Prakash, Amresh; Islam, Asimul

doi:10.1016/j.molliq.2022.121120

Cited by 5 publications

(5 citation statements)

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“…The intrinsic fluorescence (IF) of proteins aromatic amino acids (phenylalanine, tyrosine, and tryptophan) has been used extensively to monitor folding and unfolding and changes related to pH, temperature, denaturants, and pressure. Moreover, the binding of protein with an externally provided ligand can also be measured to estimate various binding and thermodynamic parameters. , Tryptophan residue is exquisitely sensitive to any changes in the protein structure . IF of the protein is an important tool to investigate the protein–ligand binding affinities. , The quenching observed in fluorescence measurements can result from various reasons such as shuffling of the molecules, interactions amongst them, charge transfer, and formation of complexes.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis, Structural Modification, and Bioactivity Evaluation of Substituted Acridones as Potent Microtubule Affinity-Regulating Kinase 4 Inhibitors

Voura,

Anwar,

Sigala

et al. 2023

ACS Pharmacol. Transl. Sci.

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Acridones present numerous pharmacological activities, including inhibition of microtubule affinity-regulating kinase 4 (MARK4) kinase activity. To investigate structure–activity relationships and develop potent MARK4 inhibitors, derivatives of 2-methylacridone were synthesized and tested for their activity against MARK4 kinase. Selective substitutions at the nitrogen atom were accomplished by treating 2-methylacridone with alkyl halides in the presence of K2CO3. In addition, amidation of acridone acetic acid 11 with piperazine or tryptophan methyl ester followed by derivatization with various amines gave a series of new acridone derivatives. Among the tested compounds, six were identified as possessing high inhibitory activity against MARK4. The molecular modeling studies showed that the derivatives bearing piperazine or tryptophan bind well to the ATP-binding site of MARK4. The antiproliferative activity of six active compounds was evaluated against HeLa and U87MG cancer cells. Tryptophan derivatives 23a, 23b, and 23c showed significant cytotoxicity against both cell lines with EC50 values ranging from 2.13 to 4.22 μM, while derivatives bearing piperazine were found to be not cytotoxic. Additionally, compound 23a decreased the proliferation of human MDA-MB-435 and U251 cancer cells in the low micromolar range; however, it also affects the non-cancerous HGF cells. Due to their high binding affinity against MARK4, the synthesized compounds could be potential agents to target MARK4 against cancer and tauopathies.

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Section: Resultsmentioning

confidence: 99%

“…Moreover, the binding of protein with an externally provided ligand can also be measured to estimate various binding and thermodynamic parameters. 41,42 Tryptophan residue is exquisitely sensitive to any changes in the protein structure. 43 IF of the protein is an important tool to investigate the protein−ligand binding affinities.…”

Section: 2mentioning

confidence: 99%

Synthesis, Structural Modification, and Bioactivity Evaluation of Substituted Acridones as Potent Microtubule Affinity-Regulating Kinase 4 Inhibitors

Voura,

Anwar,

Sigala

et al. 2023

ACS Pharmacol. Transl. Sci.

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“…The aliquots drawn at specific time intervals from the incubated samples at 37 °C were diluted to 15 μM. The measurement of RLS was carried out using excitation wavelengths of 350 nm and an emission range of 300–400 nm with a slit width of 5 nm …”

Section: Methodsmentioning

confidence: 99%

“…ANS was added to the aliquoted protein samples in the ratio of 1:20 . The ANS fluorescence measurements were taken by a Jasco FP-8200 spectrofluorometer using an excitation wavelength of 380 nm, and the emission range was recorded between 400 and 650 . All measurements were carried out in triplicates.…”

Section: Methodsmentioning

confidence: 99%

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Understanding the Modulation of α-Synuclein Fibrillation by N-Acetyl Aspartate: A Brain Metabolite

Khan,

Waseem,

Shahid

et al. 2024

ACS Omega

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α-Synuclein (α-Syn) fibrillation is a prominent contributor to neuronal deterioration and plays a significant role in the advancement of Parkinson's Disease (PD). Considering this, the exploration of novel compounds that can inhibit or modulate the aggregation of α-Syn is a topic of significant research. This study, for the first time, elucidated the effect of N-acetyl aspartate (NAA), a brain osmolyte, on α-Syn aggregation using spectroscopic and microscopic approaches. Thioflavin T (ThT) assay revealed that a lower concentration of NAA inhibits α-Syn aggregation, whereas higher concentrations of NAA accelerate the aggregation. Further, this paradoxical effect of NAA was complemented by ANS, RLS, and the turbidity assay. The secondary structure transition was more pronounced at higher concentrations of NAA by circular dichroism, corroborating the fluorescence spectroscopic observations. Confocal microscopy also confirmed the paradoxical effect of NAA on α-Syn aggregation. Interaction studies including fluorescence quenching and molecular docking were employed to determine the binding affinity and critical residues involved in the α-Syn-NAA interaction. The explanation for this paradoxical nature of NAA could be a solvophobic effect. The results offer a profound understanding of the modulatory mechanism of α-Syn aggregation by NAA, thereby suggesting the potential role of NAA at lower concentrations in therapeutics against α-Syn aggregation-related disorders.

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Treadmill exercise with nanoselenium supplementation affects the expression of Irisin/FNDC5 and semaphorin 3A in rats exposed to cigarette smoke extract

Arabzadeh,

Shirvani,

Masjedi

et al. 2023

3 Biotech

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Molecular basis of structural stability of Irisin: A combined molecular dynamics simulation and in vitro studies for Urea-induced denaturation

Cited by 5 publications

References 62 publications

Synthesis, Structural Modification, and Bioactivity Evaluation of Substituted Acridones as Potent Microtubule Affinity-Regulating Kinase 4 Inhibitors

Synthesis, Structural Modification, and Bioactivity Evaluation of Substituted Acridones as Potent Microtubule Affinity-Regulating Kinase 4 Inhibitors

Understanding the Modulation of α-Synuclein Fibrillation by N-Acetyl Aspartate: A Brain Metabolite

Treadmill exercise with nanoselenium supplementation affects the expression of Irisin/FNDC5 and semaphorin 3A in rats exposed to cigarette smoke extract

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