Targeting Invasion-Promoting Proteases MMP-7 and MMP-14 at Remote Exosites

August 01, 2020
Events, ACS2020

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. 


Steve-Van-Doren-1Steven Van Doren, PhD 
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

Abstract

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

 


Poster Presentation

On-demand Poster (click for high-resolution)

MMPtargeting3431759_VanDoren_preview


About AIMS

The AIMS Awards program, started in 2017, is designed to support promising researchers with resources that will help advance their work. AIMS Awards target research focused on finding solutions for complex human health conditions. To date, Atomwise has funded 5 rounds of AIMS Awards, completing over 100 collaborative projects and accepting over 775 projects into the program. Applications are accepted anytime.

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