Title:Discoidin Domain Receptor 1 Inhibitors: Advances and Future Directions
for Novel Therapeutics with Aid of DNA Encoded Library Screens and Artificial
Intelligence
Volume: 23
Issue: 15
Author(s): Rahul Sanawar*, Vinodh J. Sahayasheela, Praseetha Sarath and Vipin Mohan Dan*
Affiliation:
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College
of Medicine, Bronx, NY-10461, USA
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY-
10461, USA
- Division of Microbiology, Jawaharlal Nehru Tropical Botanic Garden and Research
institute, Trivandrum, Kerala, India
Keywords:
Discoidin, domain receptor, collagen, artificial intelligence, cancer, fibrosis, kinase.
Abstract: Discoidin domain receptor (DDR) 1, a collagen binding receptor kinase, is an intensively
researched therapeutic target for cancer, fibrosis and other diseases. The majority of early known
DDR1 inhibitors targeted the ATP binding pocket of this enzyme that shares structural similarities
with other kinase pockets across the biological system. This structural similarity of DDR1 kinase
with other protein kinases often leads to “off target “toxicity issues. Understanding of uniqueness in
DDR:ATP–phosphate-binding loop (P-loop), DNA encoded library screen, structure-guided optimization
studies, and machine learning drug design platforms that come under the umbrella of artificial
intelligence has led to the discovery of a new array of inhibitors that are highly selective for DDR1
over DDR2 and other similar kinases. Most of the drug discovery platforms concentrated on the
ATP binding region of DDR1 kinase and never looked beyond this region for novel therapeutic options.
Recent findings have disclosed the kinase-independent functions of DDR1 in immune exclusion,
which resides in the extracellular collagen-binding domain, thus opening avenues for the development
of inhibitors that veer away from targeting ATP binding pockets. This recent understanding
of the functional modalities of DDR1 opens the complexity of targeting this transmembrane protein
as per its functional prominence in the respective disease and thus demands the development of
specific novel therapeutics. The perspective gives a short overview of recent developments of
DDR1 inhibitors with the aid of the latest technologies, future directions for therapeutic development,
and possibility of combinational therapeutic treatments to completely disengage functions of
DDR1.
