The recent high-resolution crystal structures of several GPCR or integrin types offer tremendous opportunities for computer-aided drug discovery/optimization approaches to discover novel and selective binders as some of our recent publications demonstrate. By combining our virtual screening, cheminformatics, and molecular dynamics simulations, with collaborative functional and structural studies, as well as chemical synthesis, we have recently contributed to the discovery of (i) a novel agonist of the kappa-opioid receptor (in collaboration with Jonathan A. Javitch at Columbia U. and Thomas Prisinzano at Kansas U.); (ii) novel positive allosteric modulators of the delta-opioid receptor (in collaboration with Neil Burford, Andy Alt, and Samuel Gerritz at BMS, Merixtell Canals and Arthur Christopoulos at Monash U., and John Traynor at U. of Michigan); (iii) a μOR-δOR heteromer-biased agonist with antinociceptive activity (in collaboration with Lakshmi Devi at Mount Sinai and Peter Hodder at Scripps), and (iv) novel antagonists of the αIIbβ3 receptor that limit conformational reorganization of the receptor, thus resulting in improved anti-platelets agents (in collaboration with Barry S. Coller at Rockefeller U. and Craig Thomas at the NIH). In particular, this latter discovery was protected by a patent application entitled: “Organic Compounds (Anti-platelet agents)” (Serial number: PCT/US2013/021749).
Negri, A., Rives, M.L., Caspers, M.J., Prisinzano, T.E., Javitch, J.A., and Filizola, M. “Discovery of a Novel Selective Kappa-Opioid Receptor Agonist Using Crystal Structure-Based Virtual Screening” Journal of Chemical Information and Modeling (2013) 53: 521-526.
Burford, N., Livingston, K., Canals, M., Ryan, M., Budenholzer, L., Han, Y., Shang, Y., Herbst, J.J., O’Connell, J., Banks, M., Zhang, L., Filizola, M., Bassoni, D., Wehrman, T., Christopoulos, A., Traynor, J., Gerritz, S., Alt, A. “Discovery, Synthesis and Molecular Pharmacology of Selective Positive Allosteric Modulators of the δ-Opioid Receptor” (2015) Journal of Medicinal Chemistry Apr 22. [Epub ahead of print]
Zhu, J., Choi, W.-S., McCoy, J.G., Negri, A., Zhu, J., Naini, S., Li, J., Shen, M., Huang, W., Bougie, D., Rasmussen, M., Aster, R., Thomas, C.J., Filizola, M., Springer, T.A., and Coller, B.S. “Structure-Guided Design of a High Affinity Platelet Integrin αIIbβ3 Receptor Antagonist That Disrupts Mg2+ Binding to the MIDAS” Science Translational Medicine (2012) 4(125):1-13.
Gomes, I., Fujita, W., Gupta, A., Saldanha, A.S., Negri, A., Pinello, C.E., Roberts, E., Filizola, M., Hodder, P., and Devi, L.A. “Identification of a μOR-δOR heteromer-biased agonist with antinociceptive activity” Natl. Acad. Sci. USA (2013) 110(29):12072-7.