Identification of DDR1 Inhibitors from Marine Compound Library Based on Pharmacophore Model and Scaffold Hopping

Area of Science:

• Biochemistry
• Pharmacology
• Medicinal Chemistry

Background:

• Ulcerative colitis (UC) is a chronic intestinal inflammatory disease.
• DDR1 kinase activity is crucial for maintaining intestinal barrier function in UC.
• Existing DDR1 inhibitors face challenges with toxicity and stability, necessitating novel drug development.

Purpose of the Study:

• To identify novel, effective, and safer DDR1 inhibitors for ulcerative colitis treatment.
• To develop a validated pharmacophore model for screening potential DDR1 inhibitors.
• To discover and optimize lead compounds from marine natural products.

Main Methods:

• Analysis of 85 DDR1 inhibitors to build a pharmacophore model.
• High-throughput virtual screening of a marine natural product database (>52,000 compounds).
• Docking, scaffold hopping, ADMET analysis, and molecular dynamics simulations for compound optimization and validation.

Main Results:

• Identified 17 potential DDR1 inhibitors from marine sources.
• Generated 1070 novel compounds via scaffold hopping, improving binding affinity and drug-like properties.
• Selected three compounds (39713a, 34346a, 34419a) with superior predicted activity, stable interactions, and favorable ADMET profiles compared to known inhibitors.

Conclusions:

• Compounds 39713a, 34346a, and 34419a demonstrate significant potential as DDR1 inhibitors.
• These compounds exhibit promising therapeutic prospects for ulcerative colitis treatment due to enhanced efficacy and drug-like properties.