Exploring the promising potential of noscapine for cancer and neurodegenerative disease therapy through inhibition of integrin-linked kinase-1
Copyright © 2024. Published by Elsevier B.V..
Integrin-linked kinase (ILK), a β1-integrin cytoplasmic domain interacting protein, supports multi-protein complex formation. ILK-1 is involved in neurodegenerative diseases by promoting neuro-inflammation. On the other hand, its overexpression induces epithelial-mesenchymal transition (EMT), which is a major hallmark of cancer and activates various factors associated with a tumorigenic phenotype. Thus, ILK-1 is considered as an attractive therapeutic target. We investigated the binding affinity and ILK-1 inhibitory potential of noscapine (NP) using spectroscopic and docking approaches followed by enzyme inhibition activity. A strong binding affinity of NP was measured for the ILK-1 with estimated Ksv (M-1) values of 1.9 × 105, 3.6 × 105, and 4.0 × 105 and ∆G0 values (kcal/mol) -6.19554, -7.8557 and -8.51976 at 298 K, 303 K, and 305 K, respectively. NP binds to ILK-1 with a docking score of -6.6 kcal/mol and forms strong interactions with active-site pocket residues (Lys220, Arg323, and Asp339). The binding constant for the interaction of NP to ILK-1 was 1.04 × 105 M-1, suggesting strong affinity and excellent ILK-1 inhibitory potential (IC50 of ∼5.23μM). Conformational dynamics of ILK-1 were also studied in the presence of NP. We propose that NP presumably inhibits ILK-1-mediated phosphorylation of various downstream signalling pathways that are involved in cancer cell survival and neuroinflammation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:262 |
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| Enthalten in: |
International journal of biological macromolecules - 262(2024), Pt 2 vom: 01. März, Seite 130146 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hakami, Mohammed Ageeli [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 27.03.2024 Date Revised 27.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ijbiomac.2024.130146 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM368552055 |
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| 100 | 1 | |a Hakami, Mohammed Ageeli |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Exploring the promising potential of noscapine for cancer and neurodegenerative disease therapy through inhibition of integrin-linked kinase-1 |
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| 500 | |a Date Revised 27.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024. Published by Elsevier B.V. | ||
| 520 | |a Integrin-linked kinase (ILK), a β1-integrin cytoplasmic domain interacting protein, supports multi-protein complex formation. ILK-1 is involved in neurodegenerative diseases by promoting neuro-inflammation. On the other hand, its overexpression induces epithelial-mesenchymal transition (EMT), which is a major hallmark of cancer and activates various factors associated with a tumorigenic phenotype. Thus, ILK-1 is considered as an attractive therapeutic target. We investigated the binding affinity and ILK-1 inhibitory potential of noscapine (NP) using spectroscopic and docking approaches followed by enzyme inhibition activity. A strong binding affinity of NP was measured for the ILK-1 with estimated Ksv (M-1) values of 1.9 × 105, 3.6 × 105, and 4.0 × 105 and ∆G0 values (kcal/mol) -6.19554, -7.8557 and -8.51976 at 298 K, 303 K, and 305 K, respectively. NP binds to ILK-1 with a docking score of -6.6 kcal/mol and forms strong interactions with active-site pocket residues (Lys220, Arg323, and Asp339). The binding constant for the interaction of NP to ILK-1 was 1.04 × 105 M-1, suggesting strong affinity and excellent ILK-1 inhibitory potential (IC50 of ∼5.23μM). Conformational dynamics of ILK-1 were also studied in the presence of NP. We propose that NP presumably inhibits ILK-1-mediated phosphorylation of various downstream signalling pathways that are involved in cancer cell survival and neuroinflammation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Cancer therapeutics | |
| 650 | 4 | |a Drug discovery | |
| 650 | 4 | |a Enzyme inhibition | |
| 650 | 4 | |a Natural products | |
| 650 | 4 | |a Neuroinflammation | |
| 650 | 4 | |a Protein kinase | |
| 650 | 7 | |a integrin-linked kinase |2 NLM | |
| 650 | 7 | |a EC 2.7.1.- |2 NLM | |
| 650 | 7 | |a Noscapine |2 NLM | |
| 650 | 7 | |a 8V32U4AOQU |2 NLM | |
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| 700 | 1 | |a Alotaibi, Bader S |e verfasserin |4 aut | |
| 700 | 1 | |a Alkhalil, Samia S |e verfasserin |4 aut | |
| 700 | 1 | |a Anwar, Saleha |e verfasserin |4 aut | |
| 700 | 1 | |a Jairajpuri, Deeba Shamim |e verfasserin |4 aut | |
| 700 | 1 | |a Hazazi, Ali |e verfasserin |4 aut | |
| 700 | 1 | |a Alsulami, Mishal Olayan |e verfasserin |4 aut | |
| 700 | 1 | |a Jawaid, Talha |e verfasserin |4 aut | |
| 700 | 1 | |a Yadav, Dharmendra Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Almasoudi, Hassan H |e verfasserin |4 aut | |
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