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

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Computational Biology

Background:

• Kinases regulate cellular functions via phosphorylation; mutations are linked to cancer.
• Existing kinase inhibitors like Crizotinib have limitations and side effects.
• Novel inhibitors are needed to overcome resistance and improve safety.

Purpose of the Study:

• To develop novel natural product-based inhibitors targeting the ROS1 Kinase Domain using Computer-Aided Drug Design (CADD).
• To identify potent inhibitors effective against both wild-type and resistant ROS1 kinase mutations.

Main Methods:

• Virtual screening of a natural product library using CADD techniques.
• Molecular fingerprints, molecular dynamics simulations, docking, and quantum calculations for structure evaluation.
• Assessment of binding affinity and interactions with ROS1 Kinase Domain and G2032R mutant.

Main Results:

• One novel structure, LIG48, showed significant binding affinity and interactions with both wild-type and G2032R mutant ROS1 Kinase Domains.
• LIG48 and Crizotinib demonstrated stable interactions within the kinase domains during 400 ns simulations.
• LIG48 exhibits potential as a potent inhibitor against ROS1 kinase, including resistant forms.

Conclusions:

• CADD techniques successfully identified LIG48 as a promising candidate for ROS1 kinase inhibition.
• LIG48 offers a potential therapeutic strategy to address resistance and side effects associated with current kinase inhibitors.
• This study highlights a viable approach for designing next-generation kinase inhibitors.