Structure-Guided Drug Discovery and Chemotype Optimization

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).

Representative Publications

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.

Jiang, J.-K. McCoy, J.G., Shen, M., LeClair, C., Huang, W., Negri, A., Li, J., Blue, R., Harrington, A., Naini,  S., David, G. III, Choi, W.-S., Volpi, E., Fernandez, J.,  Babayeva, M., Nedelman, M.A., Filizola, M., Coller, B.S., Thomas, C.G. “A novel class of ion displacement ligands as antagonists of the αIIbβ3 receptor that limit conformational reorganization of the receptor” Bioorganic & Medicinal Chemistry Letters (2014) 24(4):1148-53

Li, J., Vootukuri, S., Shang, Y., Negri, A., Jiang, J.-K., Nedelman, M., Diacovo, T.G., Filizola, M., Thomas, C.J., Coller, B.S. “RUC-4: A Novel αIIbβ3 Antagonist for Pre-hospital Therapy of Myocardial Infarction” Arteriosclerosis, Thrombosis, and Vascular Biology (2014) Aug 21. pii: ATVBAHA.114.303724.

Burford, N., Livingston, K., Canals, M., Ryan, M., Budenholzer, L., Han, Y., Shang, Y., Herbst, 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 58(10):4220-9.

Bisignano, P., Burford, N.T., Shang, Y., Marlow, B., Livingston, K.E., Fenton, A.M., Rockwell,K., Budenholzer, L., Traynor, J., Gerritz, S.W., Alt, A., and Filizola, M. “Ligand-Based Discovery of a New Scaffold for Allosteric Modulation of the mu-Opioid Receptor” (2015) Journal of Chemical Information & Modeling 55(9):1836-43

Kruegel, A.C., Gassaway, M.M., Kapoor, A., Varadi, A., Majumdar, S., Filizola, M., Javitch, J.A., Sames, D. “Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators” (2016) Journal of the American Chemical Society 138(21):6754-64

Wardman, J.H., Gomes, I., Bobeck, E.N., Stockert, J., Kapoor, A., Bisignano, P., Gupta, A., Mezei, M., Kumar, S., Filizola, M., Devi, L.A. “Identification of a small molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake” (2016) Science Signaling 9(430):ra55.

Crowley, R.S., Riley, A.P., Sherwood, A.M., Groer, C.E., Shivaperumal, N., Biscaia, M., Paton, K., Schneider, S., Provasi, D., Kivell, B.M., Filizola, M., and Prisinzano, T.E. “Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability” (2016) Journal of Medicinal Chemistry, 59(24):11027-11038

Li, J., Fukase, Y., Shang, Y., Zou, W., Munoz-Felix, J., Buitrago, L., van Agthoven, J., Zhang, X., Hara, R., Tanaka,Y., Okamoto, R.,  Yasui, T., Nakahata,  T., Imaeda, T., Aso, K.,  Zhou, Y., Locuson, C., Nesic, D., Duggan, M.,  Takagi, J., Vaughan, R., Walz, T., Hodivala-Dilke, K., Teitelbaum, S.L., Arnaout, A.M., Filizola, M., Foley, M.A., Coller, B.S. “Novel Pure αVβ3 Integrin Antagonists That Do Not Induce Receptor Extension, Prime the Receptor, or Enhance Angiogenesis at Low Concentrations” ACS Pharmacology & Translational Science (2019) 2, 6, 387-401.

Hughes, T.E.T., Del Rosario, J.S., Kapoor, A., Yazici, A. T., Fluck, E.C., Filizola, M., Rohacs, T., Moiseenkova-Bell, V.Y. “Structure-based discovery of novel TRPV5 inhibitors” (2019) ELife ; pii: e49572. doi: 10.7554/eLife.49572.

Jatiani, S.S., Christie, S., Leshchenko, V., Jain, R., Kapoor, A., Bisignano, P., Lee, C., Kaniskan, H.U., Edwards, D., Meng, F., Lagana, A., Youssef, Y., Wiestner, A., Alinari, L., Jin, J., Filizola, M., Aggarwal, A. K., Parekh, S. ““SOX11 Inhibitors Are Cytotoxic in Mantle Cell Lymphoma.” Clinical Cancer Research  (2021) Aug 15;27(16):4652-4663.

Chakraborty, S., Diberto, J., Faouzi, A., Bernhard, S., Gutridge, A., Ramsey, S., Zhou, Y., Provasi, D., Nuthikattu, N., Jilakia, R., Nelson, M.N.F., Asher, W.B., Eans, S. O., Wilson, L.L., Chintala, S.M., Filizola, M., van Rijn, R.M., Margolis, E.B., Roth, B.L., McLaughlin, J.P., Che, T., Sames, D., Javitch, J.A., Majumdar, S. “A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects” (2021) Journal of Medicinal Chemistry Sep 23;64(18):13873-13892.

Sen, S., Spasic, A., Sinha, A., Wang, J., Bush, M., Li, J., Nešić, D., Zhou, Y., Angiulli, G., Morgan, P., Salas-Estrada, L., Takagi, J., Walz, T., Coller, B., Filizola, M. “Structure-Based Discovery of a Novel Class of Small-Molecule Pure Antagonist of Integrin aVb3” (2022) Journal of Chemical Information and Modeling Oct 24. doi: 10.1021/acs.jcim.2c00999.