Structure‐based investigation of MARK4 inhibitory potential of Naringenin for therapeutic management of cancer and neurodegenerative diseases
| Autor: | Farah Anjum, Imtaiyaz Hassan, Alaa Shafie, Faizan Ahmad, Asimul Islam, Anas Shamsi, Saleha Anwar, Shama Khan |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Naringenin Conformational change Protein Conformation Molecular Dynamics Simulation Protein Serine-Threonine Kinases urologic and male genital diseases Biochemistry Serine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Neoplasms Humans Threonine Protein Kinase Inhibitors Molecular Biology Serine/threonine-specific protein kinase Binding Sites biology urogenital system Drug discovery Estrogen Antagonists Active site Neurodegenerative Diseases Cell Biology Binding constant Molecular Docking Simulation 030104 developmental biology chemistry 030220 oncology & carcinogenesis Flavanones biology.protein Protein Binding |
| Zdroj: | Journal of Cellular Biochemistry. 122:1445-1459 |
| ISSN: | 1097-4644 0730-2312 |
| Popis: | 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 × 106 M-1 obtained from fluorescence binding studies. Further, enzyme inhibition studies showed that NAG has an admirable IC50 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. |
| Databáze: | OpenAIRE |
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