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Identification of 5-nitroindazole as a multitargeted inhibitor for CDK and transferase kinase in lung cancer: a multisampling algorithm-based structural study

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Abstract

Lung cancer is the second most common cancer, which is the leading cause of cancer death worldwide. The FDA has approved almost 100 drugs against lung cancer, but it is still not curable as most drugs target a single protein and block a single pathway. In this study, we screened the Drug Bank library against three major proteins- ribosomal protein S6 kinase alpha-6 (6G77), cyclic-dependent protein kinase 2 (1AQ1), and insulin-like growth factor 1 (1K3A) of lung cancer and identified the compound 5-nitroindazole (DB04534) as a multitargeted inhibitor that potentially can treat lung cancer. For the screening, we deployed multisampling algorithms such as HTVS, SP and XP, followed by the MM\GBSA calculation, and the study was extended to molecular fingerprinting analysis, pharmacokinetics prediction, and Molecular Dynamics simulation to understand the complex’s stability. The docking scores against the proteins 6G77, 1AQ1, and 1K3A were − 6.884 kcal/mol, − 7.515 kcal/mol, and − 6.754 kcal/mol, respectively. Also, the compound has shown all the values satisfying the ADMET criteria, and the fingerprint analysis has shown wide similarities and the water WaterMap analysis that helped justify the compound’s suitability. The molecular dynamics of each complex have shown a cumulative deviation of less than 2 Å, which is considered best for the biomolecules, especially for the protein–ligand complexes. The best feature of the identified drug candidate is that it targets multiple proteins that control cell division and growth hormone mediates simultaneously, reducing the burden of the pharmaceutical industry by reducing the resistance chance.

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Acknowledgements

The authors would like to thank Jamia Millia Islamia, New Delhi, for providing computational resources and software solutions.

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  1. Computational Intelligence and Bioinformatics Laboratory, Department of Computer Science, Jamia Millia Islamia, New Delhi, 110025, India

    Shaban Ahmad & Khalid Raza

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  1. Shaban Ahmad
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SA contributed to conceptualisation, data collection/curation, analysis, writing, and extensive editing of the first draft. KR contributed to supervision, computational resources, reviewing, and editing.

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Correspondence to Khalid Raza.

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Ahmad, S., Raza, K. Identification of 5-nitroindazole as a multitargeted inhibitor for CDK and transferase kinase in lung cancer: a multisampling algorithm-based structural study. Mol Divers (2023). https://doi.org/10.1007/s11030-023-10648-0

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