Pharmacophore Synergism in Diverse Scaffold Clinches in Aurora Kinase B

Aurora kinase B (AKB) is a crucial signaling kinase with an important role in cell division. Therefore, inhibition of AKB is an attractive approach to the treatment of cancer. In the present work, extensive quantitative structure-activity relationships (QSAR) analysis has been performed using a set...

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Published in:International journal of molecular sciences 2022-11, Vol.23 (23), p.14527
Main Authors: Masand, Vijay H, Al-Hussain, Sami A, Rathore, Mithilesh M, Thakur, Sumer D, Akasapu, Siddhartha, Samad, Abdul, Al-Mutairi, Aamal A, Zaki, Magdi E A
Format: Article
Language:English
Subjects:
Aurora kinase
Aurora Kinase B
Biological activity
Cancer
Cell cycle
Cell division
Chromosomes
Cyclin-dependent kinases
Datasets
Kinases
Lipophilic
Mathematical models
Molecular Docking Simulation
Nitrogen
Pharmacology
Pharmacophore
pharmacophore modeling
QSAR
Quantitative Structure-Activity Relationship
Structure-activity relationships
Tumors
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Summary:Aurora kinase B (AKB) is a crucial signaling kinase with an important role in cell division. Therefore, inhibition of AKB is an attractive approach to the treatment of cancer. In the present work, extensive quantitative structure-activity relationships (QSAR) analysis has been performed using a set of 561 structurally diverse aurora kinase B inhibitors. The Organization for Economic Cooperation and Development (OECD) guidelines were used to develop a QSAR model that has high statistical performance (R = 0.815, Q = 0.808, R = 0.814, CCC = 0.899). The seven-variable-based newly developed QSAR model has an excellent balance of external predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The QSAR analysis successfully identifies not only the visible pharmacophoric features but also the hidden features. The analysis indicates that the lipophilic and polar groups-especially the H-bond capable groups-must be present at a specific distance from each other. Moreover, the ring nitrogen and ring carbon atoms play important roles in determining the inhibitory activity for AKB. The analysis effectively captures reported as well as unreported pharmacophoric features. The results of the present analysis are also supported by the reported crystal structures of inhibitors bound to AKB.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms232314527