In silico design of natural-based structures as drug candidates to inhibit ROS1 protein.

Kinases modulate protein activities through phosphate group transfers, regulating cellular functions. Mutations in kinases are related to cancer initiation, progression, and recurrence. Kinase inhibitors, such as Crizotinib, have demonstrated efficacy against specific cancers; however, limitations and adverse effects necessitate the development and discovery of novel, potent inhibitors. This study employs Computer-Aided Drug Design techniques to develop natural product-based structures targeting the ROS1 Kinase Domain. Molecular fingerprints, molecular dynamics simulations, Docking, and quantum calculations are utilized for virtual screening and structure evaluation. A compound library is constructed, and candidates are screened based on Computer-Aided Drug Design techniques. Notably, one structure, named LIG48, demonstrated a substantial binding affinity and interactions with the ROS1 Kinase Domain and its mutant (G2032R ROS1 kinase domain). In addition, LIG48 and crizotinib remained within the mutated and wild-type ROS1 kinase domains in all replicas, for a total simulation time of 400 ns for each system. This research presents a promising and potentially effective route for designing kinase inhibitors that could address resistance and side effects associated with existing therapies.