Identification of 5-nitroindazole as a multitargeted inhibitor for CDK and transferase kinase in lung cancer: a
1Computational Intelligence and Bioinformatics Laboratory, Department of Computer Science, Jamia Millia Islamia, New Delhi, 110025, India.
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.
Insights
Researchers identified 5-nitroindazole as a promising multi-targeted drug candidate for lung cancer. This compound inhibits multiple proteins simultaneously, potentially offering a more effective treatment and reducing drug resistance.
Area of Science:
- Oncology
- Pharmacology
- Computational Chemistry
Background:
- Lung cancer is a leading cause of cancer death globally, with current treatments often targeting single pathways, leading to limited efficacy and resistance.
- Existing FDA-approved drugs for lung cancer, despite their number, have not achieved a cure due to the complexity of the disease.
Purpose of the Study:
- To screen the Drug Bank library for novel compounds targeting key lung cancer proteins.
- To identify a multi-targeted inhibitor capable of simultaneously blocking multiple oncogenic pathways in lung cancer.
Main Methods:
- Virtual screening of the Drug Bank library against ribosomal protein S6 kinase alpha-6 (6G77), cyclic-dependent protein kinase 2 (1AQ1), and insulin-like growth factor 1 (1K3A) using HTVS, SP, and XP algorithms.
- Molecular docking, MM\GBSA calculations, molecular fingerprinting, pharmacokinetics prediction, and Molecular Dynamics simulations were employed to assess compound stability and suitability.
- ADMET criteria and WaterMap analysis were used to evaluate the pharmacokinetic properties and binding interactions of the identified compound.
Main Results:
- 5-nitroindazole (DB04534) was identified as a potent multi-targeted inhibitor with significant docking scores against 6G77 (-6.884 kcal/mol), 1AQ1 (-7.515 kcal/mol), and 1K3A (-6.754 kcal/mol).
- The compound demonstrated favorable ADMET properties and structural stability, with molecular dynamics simulations showing cumulative deviations below 2 Å.
- Fingerprint analysis indicated broad similarities, and WaterMap analysis supported the compound's suitability for therapeutic application.
Conclusions:
- 5-nitroindazole is a promising drug candidate for lung cancer treatment due to its ability to simultaneously target multiple proteins involved in cell division and growth.
- This multi-targeted approach may overcome drug resistance mechanisms and reduce the development burden for the pharmaceutical industry.
- The identified compound represents a potential advancement in lung cancer therapy through rational drug design and computational screening.
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