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Instruments / Technical Area	Publication Details	Published
	Ugi-tetrazole-derived α-aminomethyl scaffolds reveal unexpected binding modes in SARS-CoV-2 3CLpro Robin Van Der Straat , Rick Oerlemans , Yingying Cong , Jeffrey Boxma , Radu G. Bulai , Clàudia Río-Bergé , Lizbe Koekemoer , Tryfon Zarganes Tzitzikas , Zhirui Guan , Peter G. Marples , Fulvio Reggiori , Matthew Groves , Alexander Dömling Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.5c00773 Open Access Show Abstract ▼ Abstract: The SARS-CoV-2 main protease (3CLpro) is a well-validated target for structure-guided inhibitor discovery. Here, we report α-aminomethyl tetrazole inhibitors accessed via the Ugi tetrazole multicomponent reaction (UT-4CR), enabling rapid exploration of non-classical chemical space. Initial design and modeling suggested a binding mode analogous to Ugi-derived (U-4CR) 3CLpro inhibitors, with heteroaromatic substituents engaging the S1 pocket. However, crystallographic analysis revealed an unexpected binding orientation in which the tetrazole core itself occupies the S1 pocket and forms the key interaction with His163, while the modeled substituents are solvent-exposed. This revised binding mode rationalizes the observed structure–activity relationships. Installation of an electrophilic warhead yielded covalent inhibitors with sub-micromolar enzymatic potency, and lead compound 2a displayed modest antiviral activity in infected cells. These results highlight UT-4CR-derived tetrazoles as a platform for probing the 3CLpro binding space and underscore the importance of early crystallographic validation.	Mar 2026
I03-Macromolecular Crystallography	Covalent inhibitors of S100A4 block the formation of a pro-metastasis non-muscle myosin 2A complex Charline Giroud , Tamas Szommer , Carmen Coxon , Octovia Monteiro , Thomas Grimes , Tryfon Zarganes-Tzitzikas , Thomas Christott , James Bennett , Karly Buchan , Paul E. Brennan , Oleg Fedorov Journal Of Medicinal Chemistry 4 DOI: 10.1021/acs.jmedchem.4c01320 Diamond Proposal Number(s): [19301] Open Access Show Abstract ▼ Abstract: The S100 protein family functions as protein–protein interaction adaptors regulated by Ca2+ binding. Formation of various S100 complexes plays a central role in cell functions, from calcium homeostasis to cell signaling, and is implicated in cell growth, migration, and tumorigenesis. We established a suite of biochemical and cellular assays for small molecule screening based on known S100 protein–protein interactions. From 25 human S100 proteins, we focused our attention on S100A4 because of its well-established role in cancer progression and metastasizes by interacting with nonmuscle myosin II (NMII). We identified several potent and selective inhibitors of this interaction and established the covalent nature of binding, confirmed by mass spectrometry and crystal structures. 5b showed on-target activity in cells and inhibition of cancer cell migration. The identified S100A4 inhibitors can serve as a basis for the discovery of new cancer drugs operating via a novel mode of action.	Oct 2024
I03-Macromolecular Crystallography	Discovery and development strategies for SARS-CoV-2 NSP3 macrodomain inhibitors Marion Schuller , Tryfon Zarganes-Tzitzikas , James Bennett , Stephane De Cesco , Daren Fearon , Frank Von Delft , Oleg Fedorov , Paul E. Brennan , Ivan Ahel Pathogens 12 DOI: 10.3390/pathogens12020324 Diamond Proposal Number(s): [23459] Open Access Show Abstract ▼ Abstract: The worldwide public health and socioeconomic consequences caused by the COVID-19 pandemic highlight the importance of increasing preparedness for viral disease outbreaks by providing rapid disease prevention and treatment strategies. The NSP3 macrodomain of coronaviruses including SARS-CoV-2 is among the viral protein repertoire that was identified as a potential target for the development of antiviral agents, due to its critical role in viral replication and consequent pathogenicity in the host. By combining virtual and biophysical screening efforts, we discovered several experimental small molecules and FDA-approved drugs as inhibitors of the NSP3 macrodomain. Analogue characterisation of the hit matter and crystallographic studies confirming binding modes, including that of the antibiotic compound aztreonam, to the active site of the macrodomain provide valuable structure–activity relationship information that support current approaches and open up new avenues for NSP3 macrodomain inhibitor development.	Feb 2023

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