Exploring the promising potential of noscapine for cancer and neurodegenerative disease therapy through inhibition of integrin-linked kinase-1
- Authors
- Hakami, Mohammed Ageeli; Alotaibi, Bader S.; Alkhalil, Samia S.; Anwar, Saleha; Jairajpuri, Deeba Shamim; Hazazi, Ali; Alsulami, Mishal Olayan; Jawaid, Talha; Yadav, Dharmendra Kumar; Almasoudi, Hassan H.
- Issue Date
- Mar-2024
- Publisher
- ELSEVIER
- Keywords
- Neuroinflammation; Protein kinase; Natural products; Drug discovery; Cancer therapeutics; Enzyme inhibition
- Citation
- INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, v.262
- Journal Title
- INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
- Volume
- 262
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/91053
- DOI
- 10.1016/j.ijbiomac.2024.130146
- ISSN
- 0141-8130
1879-0003
- Abstract
- Integrin-linked kinase (ILK), a beta 1-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 x 10(5), 3.6 x 10(5), and 4.0 x 10(5) and triangle G(0) 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 x 10(5) M-1, suggesting strong affinity and excellent ILK-1 inhibitory potential (IC50 of similar to 5.23 mu M). 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.
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