ArticleACS medicinal chemistry letters2026
Ugi-Tetrazole-Derived α‑Aminomethyl Scaffolds Reveal Unexpected Binding Modes in SARS-CoV‑2 3CLpro.
Article in ACS medicinal chemistry letters, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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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
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