In silico discovery of novel Retinoic Acid Receptor agonist structures
1 Structural Biology, Skirball Institute of Biomolecular Medicine, New York, USA
2 Division of Molecular Endocrinology, Department of Medicine and Department of Pharmacology New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
3 Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road (TPC-28), La Jolla CA, 92037, USA
BMC Structural Biology 2001, 1:1 doi:10.1186/1472-6807-1-1Published: 4 June 2001
Several Retinoic Acid Receptors (RAR) agonists have therapeutic activity against a variety of cancer types; however, unacceptable toxicity profiles have hindered the development of drugs. RAR agonists presenting novel structural and chemical features could therefore open new avenues for the discovery of leads against breast, lung and prostate cancer or leukemia.
We have analysed the induced fit of the active site residues upon binding of a known ligand. The derived binding site models were used to dock over 150,000 molecules in silico (or virtually) to the structure of the receptor with the Internal Coordinates Mechanics (ICM) program. Thirty ligand candidates were tested in vitro.
Two novel agonists resulting from the predicted receptor model were active at 50 nM. One of them displays novel structural features which may translate into the development of new ligands for cancer therapy.