At the American Chemical Society Fall 2020 Virtual Meeting & Expo, several Atomwise members and partners were selected to present their research and work. Learn what our Atoms have been working on below and visit Atomwise at ACS Fall 2020 Virtual Meeting & Expo for other presentation sessions.
University of Missouri
Atomwise Collaborator: Denzil Bernard, PhD and Jeff Warrington, PhD
Other Collaborators: Martin Alcantar, Carly Troupe, Cole McKay, Yan G. Fulcher, Rama K. Koppisetti
Title: Targeting Invasion-Promoting Proteases MMP-7 and MMP-14 at Remote Exosites
Division: MEDI
Migration of tumor cells in cancer metastasis is promoted by matrix metalloproteinases (MMPs) -7 and -14. Selectivity in targeting MMPs is sought for more potency and fewer side effects, but is hard to attain due to the high conservation of the active sites. Fortunately, MMP-7 and MMP-14 have distinctive remote binding sites for glycosaminoglycans (GAGs) and collagen, respectively. We located these binding sites using NMR and site-directed mutagenesis. We identified an attractive pocket in the MMP-7 catalytic domain within the remote GAG binding site. We chose a pocket within the collagen-binding site and a nearby pocket in the hemopexin-like (HPX) domain of MMP-14. We screened for binders to these pockets in silico by applying a proprietary AI strategy to a virtual library of over 6 million compounds. For each pocket, we chose three to six dozen in silico binders with diverse scaffolds. We screened for binding using ligand-detected NMR, specifically a line broadening assay of binding to proMMP-7 and saturation-transfer difference assay of binding to the HPX domain of MMP-14. At least one in three of the compounds screened appear to be binding hits. This suggests the potential druggability of these remote GAG-binding and protein binding sites, as well as the success in combining the AI screen with follow-up by NMR.
Support: Hirshberg Foundation for Pancreatic Cancer Research and MU Research Council