ROS1 kinase inhibition reimagined: identifying repurposed drug via virtual screening and molecular dynamics simulations for cancer therapeutics.

ABSTRACT

Precision medicine has revolutionized modern cancer therapeutic management by targeting specific molecular aberrations responsible for the onset and progression of tumorigenesis. ROS proto-oncogene 1 (ROS1) is a receptor tyrosine kinase (RTK) that can induce tumorigenesis through various signaling pathways, such as cell proliferation, survival, migration, and metastasis. It has emerged as a promising therapeutic target in various cancer types. However, there is very limited availability of specific ROS1 inhibitors for therapeutic purposes. Exploring repurposed drugs for rapid and effective treatment is a useful approach. In this study, we utilized an integrated approach of virtual screening and molecular dynamics (MD) simulations of repurposing existing drugs for ROS1 kinase inhibition. Using a curated library of 3648 FDA-approved drugs, virtual screening identified drugs capable of binding to ROS1 kinase domain. The results unveil two hits, Midostaurin and Alectinib with favorable binding profiles and stable interactions with the active site residues of ROS1. These hits were subjected to stability assessment through all-atom MD simulations for 200 ns. MD results showed that Midostaurin and Alectinib were stable with ROS1. Taken together, the study showed a rational framework for the selection of repurposed Midostaurin and Alectinib with ROS1 inhibitory potential for therapeutic management after further validation.