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Published on: December 7, 2014
An In Silico Approach to Uncover Selective JAK1 Inhibitors for Breast Cancer from Life Chemicals Database
Sruthy Sathish1, Honglae Sohn2, Thirumurthy Madhavan3
1Computational Biology Lab, Department of Genetic Engineering, School of Bioengineering, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, 603203, Tamil Nadu, India.
Abstract:
JAK1, a key regulator of multiple oncogenic pathways, is a sought-out target, and its expression in immune cells and tumour-infiltrating lymphocytes (TILs) is associated with a favorable prognosis in breast cancer. JAK1 activates IL-6 via ERBB2 receptor tyrosine kinase signalling and promotes metastatic cancer and STAT3 activation in breast cancer cells. Hence, targeting JAK1 in breast cancer is being explored as a potential therapeutic strategy. A comprehensive in silico approach was utilised in this study to identify selective JAK1 inhibitors from the Life chemicals database. First, we utilised an anticancer focussed library and performed molecular docking to screen against JAK1 protein. The top 10 compounds from docking were taken for cross-docking, to assess the selectivity towards JAK1 target. Lipinski's RO5 was checked for eliminating the compounds that violate rules. Toxicity, biological activity and reactivity for the identified best compounds were predicted by Protox-II server, PASS server and cDFT analysis respectively. MD simulations were carried out to examine the stability and dynamic behaviour of the top leads, including the long-term stability of the ligand-receptor complex and any conformational changes. Lastly, the MM/PBSA method was used to determine the binding free energy of the protein-ligand complex. Our in silico approach has yielded a promising set of compounds F2638-0133, F3408-0020 and F5833-7435 with the potential to selectively target JAK1, a critical player in breast cancer progression. The docking, simulation and MM/PBSA results were compared with standard drug abrocitinib. Identified compounds exhibit favorable binding interactions, electronic properties and robust stability profiles compared to standard drug, making them promising leads for further experimental validation.
Insights
This study identified novel compounds targeting JAK1, a key protein in breast cancer progression. These selective JAK1 inhibitors show promise for future therapeutic development and experimental validation.
Area of Science:
- Oncology
- Computational Chemistry
- Drug Discovery
Background:
- Janus kinase 1 (JAK1) is crucial in oncogenic pathways and its expression in immune cells correlates with better breast cancer prognosis.
- JAK1 signaling, particularly through IL-6 and ERBB2, promotes breast cancer metastasis and STAT3 activation.
- Targeting JAK1 presents a potential therapeutic strategy for breast cancer treatment.
Purpose of the Study:
- To identify selective JAK1 inhibitors using a comprehensive in silico approach.
- To screen chemical libraries for compounds with potential anticancer activity against JAK1.
- To evaluate the selectivity, stability, and binding affinity of identified JAK1 inhibitors.
Main Methods:
- In silico screening using molecular docking against JAK1.
- Cross-docking for selectivity assessment and Lipinski's Rule of Five (RO5) for drug-likeness.
- In silico ADMET prediction (Protox-II), biological activity prediction (PASS), and reactivity analysis (cDFT).
- Molecular dynamics (MD) simulations and MM/PBSA calculations for binding free energy determination.
Main Results:
- Identified three promising selective JAK1 inhibitors: F2638-0133, F3408-0020, and F5833-7435.
- These compounds demonstrated favorable binding interactions and stability profiles compared to the standard drug abrocitinib.
- In silico analyses confirmed the potential of these compounds for selective JAK1 targeting.
Conclusions:
- The identified compounds are promising lead candidates for selective JAK1 inhibition in breast cancer.
- Further experimental validation is warranted to confirm the therapeutic potential of these novel inhibitors.
- This study highlights the efficacy of in silico methods in accelerating drug discovery for targeted cancer therapies.
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