Identification of Flavonoids as Putative ROS-1 Kinase Inhibitors Using Pharmacophore Modeling for NSCLC Therapeutics

Area of Science:

• Oncology
• Pharmacology
• Computational Chemistry

Background:

• Non-small cell lung cancer (NSCLC) is a significant cause of cancer mortality.
• ROS1 tyrosine kinase is a key oncogenic driver in a subset of NSCLC patients.
• Resistance to ROS1 inhibitors like crizotinib, often due to the Gly2032Arg mutation, necessitates novel therapeutic strategies.

Purpose of the Study:

• To identify novel inhibitors targeting both wild-type (WT) and mutant (MT) ROS1 kinase domains.
• To develop and validate a pharmacophore model based on lorlatinib's interaction with ROS1.
• To screen for potential drug-like compounds from the TimTec flavonoids database.

Main Methods:

• Development of a receptor-ligand pharmacophore model for ROS1.
• Virtual screening of the TimTec flavonoids database against WT and MT ROS1.
• Molecular docking simulations of identified hits with WT and MT ROS1.
• Molecular dynamics simulations and MM/PBSA binding free energy calculations.

Main Results:

• A pharmacophore model was successfully developed and utilized for virtual screening.
• Ten flavonoids showed higher docking scores than lorlatinib against WT and MT ROS1.
• One flavonoid (Hit) exhibited superior binding free energy compared to lorlatinib and demonstrated no steric clashes with Arg2032.
• The Hit compound binds within the ROS1 selectivity pocket.

Conclusions:

• A novel flavonoid compound has been identified as a potent inhibitor of both WT and MT ROS1.
• This Hit compound shows promise as a potential therapeutic agent for NSCLC, including cases with resistance mutations.
• The findings support the use of pharmacophore modeling and virtual screening for drug discovery in oncology.