Structure-guided identification of potent inhibitors of ROS1 kinase for therapeutic development against non-small cell lung cancer

Abstract

Proto-oncogene tyrosine-protein kinase ROS (ROS1) is a member of the sevenless receptor, which affects epithelial cell differentiation and is highly expressed in a variety of tumor cells. The elevated expression and dysfunction of ROS1 have been involved in various malignancies, such as non-small cell lung cancer (NSCLC), stomach cancer, ovarian, breast cancer, cholangiocarcinoma, colorectal cancer, adenosarcoma, oesophageal cancer, etc. ROS1 has been postulated as a potential drug target in anticancer therapeutics. In this study, we carried out a virtual screening of phytochemicals against ROS1 to identify its potential inhibitors. The virtual screening process was performed on the ROS1 structure, where two phytochemicals, Helioscopinolide C and Taiwanin C, were identified. These compounds resulted from filters like Lipinski rule of five, PAINS filter, binding affinities values, and all-atom molecular dynamics (MD) simulations followed by principal component analysis (PCA) and essential dynamics. The findings of this study highlight the role of ROS1 in multiple physiological candidates and its therapeutic targeting using phytochemicals. This study suggests Helioscopinolide C and Taiwanin C as potential compounds for therapeutic development targeting ROS1-associated non-small cell lung cancer for clinical applications. Further in vitro and in vivo experiments are required to validate these findings.

Communicated by Ramaswamy H. Sarma

Keywords:

• Proto-oncogene tyrosine-protein kinase ROS
• non-small cell lung cancer
• drug discovery
• virtual screening
• molecular dynamics simulation

Acknowledgements

M.S.K. acknowledges the generous support from the Research Supporting project (RSP2023R352) by the King Saud University, Riyadh, Kingdon of Saudi Arabia.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author’s contribution

Mohd Shahnwaz Khan: Writing-original draft, Data Analysis, Investigation; Nojood Altwaijry: Visualization, software, Data validation, writing-original draft; Moneera Saud Al-Bagmi: Visualization, software, Writing-review and editing; Nouf Omar Alafaleq: Writing-review and editing, Funding acquisition, Majed S. Alokail: Data curation, Writing-review and editing; Moyad Shahwan: Data Curation, Data Validation, Anas Shamsi: Conceptualisation, Software, Data Curation, Methodology, Resources, formal analysis, Project Administration.