Enhancing Drug Repurposing with Consensus Docking: Discovery of Novel Discoidin Domain Receptor 1 Inhibitors

Area of Science:

• Oncology
• Pharmacology
• Drug Discovery

Background:

• Developing novel oncology drugs is challenging due to high costs and long timelines.
• Drug repurposing offers an efficient strategy by utilizing existing compounds for new therapeutic applications.
• Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase, is a promising target for solid tumor treatment.

Purpose of the Study:

• To identify novel, structurally distinct DDR1 inhibitors using an in-house consensus docking method (ESSENCE-Dock).
• To validate potential DDR1 inhibitors through biochemical and cellular assays.
• To demonstrate the efficacy of consensus-based virtual screening for drug repurposing in oncology.

Main Methods:

• Virtual screening of the DrugBank database using ESSENCE-Dock.
• Fingerprint dissimilarity analysis against known DDR1 inhibitors to ensure novelty.
• Biochemical IC50 assays, molecular dynamics simulations, and cell-based assays for validation.

Main Results:

• Three novel DDR1 inhibitors with nanomolar potency were identified and validated.
• Molecular dynamics simulations confirmed stable binding of inhibitors to the DDR1 active site.
• Validated inhibitors demonstrated efficacy in blocking DDR1 signaling and reducing cancer cell migration.

Conclusions:

• The consensus-based virtual screening approach is effective for drug repurposing in oncology.
• This method successfully identified novel DDR1 inhibitors with therapeutic potential.
• The findings highlight a streamlined approach to oncology drug development.