Evaluation of pyrazolopyrimidine derivatives as microtubule affinity regulating kinase 4 inhibitors: Towards therapeutic management of Alzheimer’s disease

Naqvi, Ahmad Abu Turab; Jairajpuri, Deeba Shamim; Noman, Omar M.; Hussain, Afzal; Islam, Asimul; Ahmad, Faizan; Alajmi, Mohamed F.; Hassan, Md. Imtaiyaz

doi:10.1080/07391102.2019.1666745

Cited by 40 publications

(21 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…11 The structure was re-processed, and refined on Swiss PDB Viewer. 40 This correlated by removing crystallographic waters, remodeling the missing side chain, and adding hydrogens atoms to the polar groups.…”

Section: Data Setsmentioning

confidence: 99%

Structure‐based investigation of MARK4 inhibitory potential of Naringenin for therapeutic management of cancer and neurodegenerative diseases

Anwar

Khan

Shamsi

et al. 2021

J of Cellular Biochemistry

Self Cite

View full text Add to dashboard Cite

MAP/microtubule affinity-regulating kinase 4 (MARK4) is a member of serine/threonine kinase family and considered an attractive drug target for many diseases. Screening of Indian Medicinal Plants, Phytochemistry, and Therapeutics (IMPPAT) using virtual high-throughput screening coupled with enzyme assay suggested that Naringenin (NAG) could be a potent inhibitor of MARK4. Structure-based molecular docking analysis showed that NAG binds to the critical residues found in the active site pocket of MARK4. Furthermore, molecular dynamics (MD) simulation studies for 100 ns have delineated the binding mechanism of NAG to MARK4. Results of MD simulation suggested that binding of NAG further stabilizes the structure of MARK4 by forming a stable complex. In addition, no significant conformational change in the MARK4 structure was observed. Fluorescence binding and isothermal titration calorimetric measurements revealed an excellent binding affinity of NAG to MARK4 with a binding constant (K) = 0.13 × 10 6 M −1 obtained from fluorescence binding studies. Further, enzyme inhibition studies showed that NAG has an admirable IC 50 value of 4.11 µM for MARK4. Together, these findings suggest that NAG could be an effective MARK4 inhibitor that can potentially be used to treat cancer and neurodegenerative diseases.

show abstract

Section: Data Setsmentioning

confidence: 99%

Structure‐based investigation of MARK4 inhibitory potential of Naringenin for therapeutic management of cancer and neurodegenerative diseases

Anwar

Khan

Shamsi

et al. 2021

J of Cellular Biochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Atomic coordinates of human MARK4 were taken from the Protein Data Bank (PDB ID: 5ES1, [48]) and refined through the Swiss PDB Viewer and the MGL tools [49]. Hydrogen atoms were added to the polar groups in the protein along with the Kollman charges using the Molecular Graphics Laboratory Tools.…”

Section: Molecular Dockingmentioning

confidence: 99%

MARK4 Inhibited by AChE Inhibitors, Donepezil and Rivastigmine Tartrate: Insights into Alzheimer’s Disease Therapy

et al. 2020

Self Cite

View full text Add to dashboard Cite

Microtubule affinity-regulating kinase (MARK4) plays a key role in Alzheimer’s disease (AD) development as its overexpression is directly linked to increased tau phosphorylation. MARK4 is a potential drug target of AD and is thus its structural features are employed in the development of new therapeutic molecules. Donepezil (DP) and rivastigmine tartrate (RT) are acetylcholinesterase (AChE) inhibitors and are used to treat symptomatic patients of mild to moderate AD. In keeping with the therapeutic implications of DP and RT in AD, we performed binding studies of these drugs with the MARK4. Both DP and RT bound to MARK4 with a binding constant (K) of 107 M−1. The temperature dependency of binding parameters revealed MARK−DP complex to be guided by static mode while MARK−RT complex to be guided by both static and dynamic quenching. Both drugs inhibited MARK4 with IC50 values of 5.3 μM (DP) and 6.74 μM (RT). The evaluation of associated enthalpy change (ΔH) and entropy change (ΔS) implied the complex formation to be driven by hydrogen bonding making it seemingly strong and specific. Isothermal titration calorimetry further advocated a spontaneous binding. In vitro observations were further complemented by the calculation of binding free energy by molecular docking and interactions with the functionally-important residues of the active site pocket of MARK4. This study signifies the implications of AChE inhibitors, RT, and DP in Alzheimer’s therapy targeting MARK4.

show abstract

“…Such an assembly process requires the accumulation of acetylated α-tubulin on the microtubules to create optimal sites near the endoplasmic reticulum [ 17 , 18 ]. Microtubule affinity regulating kinases (MARKs), which have four family members and share a similar structure, can phosphorylate microtubule-associated proteins (MAPs) such as MAP2, MAP4 as well as tau, thereby promoting microtubule dynamics [ 15 , 19 , 20 ]. MARK4 participates in the activation of the NLRP3 inflammasome by driving it to the microtubule-organizing center, leading to the formation of one large inflammasome speck complex [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Microtubule affinity regulating kinase 4 promoted activation of the NLRP3 inflammasome-mediated pyroptosis in periodontitis

Wang

et al. 2021

Journal of Oral Microbiology

View full text Add to dashboard Cite

Background Microtubule dynamics plays a crucial role in the spatial arrangement of cell organelles and activation of the NLRP3 inflammasome. Purpose This study aimed to explore whether microtubule affinity regulating kinase 4 (MARK4) can be a therapeutic target of periodontitis by affecting microtubule dynamics and NLRP3 inflammasome-mediated pyroptosis in macrophages. Materials and Methods The NLRP3 inflammasome-related genes and MARK4 were measured in the healthy and inflamed human gingival tissues. Bone marrow-derived macrophages (BMDMs) were infected with Porphyromonas gingivalis, while the MARK4 inhibitors (OTSSP167 and Compound 50) and small interference RNA were utilized to restrain MARK4. Apoptosis-associated speck-like protein (ASC) speck was detected by confocal, and levels of interleukin-1β (IL-1β), as well as IL-18, were assessed by ELISA. Results Increased staining and transcription of MARK4, NLRP3, ASC, and Caspase-1 were observed in the inflamed gingiva. P. gingivalis infection promoted MARK4 expression and the NLRP3 inflammasome in BMDMs. Inhibition of MARK4 decreased LDH release, IL-1β and IL-18 production, ASC speck formation, and the pyroptosis-related genes transcription. Furthermore, MARK4 inhibition reduced microtubule polymerization and acetylation in P. gingivalis- infected BMDMs. Conclusions MARK4 promoted NLRP3 inflammasome activation and pyroptosis in P. gingivalis- infected BMDMs by affecting microtubule dynamics. MARK4 inhibition might be a potential target in regulating the NLRP3 inflammasome during periodontitis progress.

show abstract

Evaluation of pyrazolopyrimidine derivatives as microtubule affinity regulating kinase 4 inhibitors: Towards therapeutic management of Alzheimer’s disease

Cited by 40 publications

References 44 publications

Structure‐based investigation of MARK4 inhibitory potential of Naringenin for therapeutic management of cancer and neurodegenerative diseases

Structure‐based investigation of MARK4 inhibitory potential of Naringenin for therapeutic management of cancer and neurodegenerative diseases

MARK4 Inhibited by AChE Inhibitors, Donepezil and Rivastigmine Tartrate: Insights into Alzheimer’s Disease Therapy

Microtubule affinity regulating kinase 4 promoted activation of the NLRP3 inflammasome-mediated pyroptosis in periodontitis

Contact Info

Product

Resources

About