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Development of Novel Human Aggrecanse-2 Dual-Binding Bis-Squaramide Inhibitors

dc.contributor.authorRatto, Amanda
dc.date.accessioned2025-03-12T12:38:10Z
dc.date.available2025-03-12T12:38:10Z
dc.date.issued2025-03-12
dc.date.submitted2025-03-11
dc.description.abstractOsteoarthritis (OA) is a degenerative joint disease that affects millions of individuals worldwide. OA is characterized by the breakdown of articular cartilage, including the proteoglycan aggrecan, which plays a crucial role in enabling cartilage to withstand compressive loads. A Disintegrin and Metalloproteinase with Thrombospondin Motifs-5 (ADAMTS-5; aggrecanase-2), has been reported to be the predominant aggrecanase in mice, and in vitro studies revealed ADAMTS-5 exhibits high efficiency at cleaving aggrecan. Although no disease modifying OA drugs have been developed, it is hypothesized that inhibitors against ADAMTS-5 could slow the progression of OA. Typical inhibitors of ADAMTS-5 include zinc-binding groups (ZBGs) that interact with the catalytic zinc. Recently, an exosite that inhibitors can target has been identified at a nearby domain, not within the catalytic site. Here we present the development of novel potential dual-binding inhibitors which aim to target both the catalytic site and exosite of ADAMTS-5. The inhibitors investigated in this thesis incorporate a squaramide nucleus, which is an excellent molecular scaffold due to its ease of derivatization, known synthetic pathways, and commercial availability. To identify potential dual-binding bis-squaramide inhibitors, a large in silico library was constructed, consisting of the squaramide nucleus linking potential exosite binding groups and ZBGs. Numerous computational techniques were utilized to identify inhibitors, including molecular docking to evaluate potential interactions with both the binding pocket and exosite of ADAMTS-5, as well as molecular dynamics simulations to assess inhibitor stability and predict binding affinities. The four bis-squaramide molecules identified from the computational screening were successfully synthesized using a one-pot, microwave-assisted synthetic approach, which facilitated a high-throughput process through reaction automation. A range of bis-squaramide compounds were enzymatically screened with micromolar IC50’s for ADAMTS-5.
dc.identifier.urihttps://hdl.handle.net/10012/21500
dc.language.isoen
dc.pendingfalse
dc.publisherUniversity of Waterlooen
dc.subjectosteoarthritis
dc.subjectsquaric acid
dc.subjectsquaramide
dc.subjectaggrecanase-2
dc.subjectADAMTS-5
dc.subjectcomputer-aided drug design
dc.titleDevelopment of Novel Human Aggrecanse-2 Dual-Binding Bis-Squaramide Inhibitors
dc.typeMaster Thesis
uws-etd.degreeMaster of Science
uws-etd.degree.departmentChemistry
uws-etd.degree.disciplineChemistry
uws-etd.degree.grantorUniversity of Waterlooen
uws-etd.embargo.terms2 years
uws.contributor.advisorHonek, John
uws.contributor.affiliation1Faculty of Science
uws.peerReviewStatusUnrevieweden
uws.published.cityWaterlooen
uws.published.countryCanadaen
uws.published.provinceOntarioen
uws.scholarLevelGraduateen
uws.typeOfResourceTexten

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