9QD5

Crystal structure of SARS-CoV-2 main protease in complex with RS222C

This is a non-PDB format compatible entry.

Summary for 9QD5

• Entry DOI: 10.2210/pdb9qd5/pdb
• Descriptor: 3C-like proteinase nsp5, DIMETHYL SULFOXIDE, SODIUM ION, ... (5 entities in total)
• Functional Keywords: protease, sars-cov-2, 3clpro, complex, covalent, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 68270.18

Authors

Oerlemans, R.,van der Straat, R.,Marples, P.,Koekemoer, L.,Domling, A.,Groves, M.R. (deposition date: 2025-03-06, release date: 2026-03-18, Last modification date: 2026-05-20)

Primary citation

van der Straat, R.,Oerlemans, R.,Cong, Y.,Boxma, J.,Bulai, R.G.,Rio-Berge, C.,Koekemoer, L.,Zarganes Tzitzikas, T.,Guan, Z.,Marples, P.G.,Reggiori, F.,Groves, M.,Domling, A.
Ugi-Tetrazole-Derived alpha ‐Aminomethyl Scaffolds Reveal Unexpected Binding Modes in SARS-CoV‐2 3CLpro.
Acs Med.Chem.Lett., 17:856-865, 2026

PubMed 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 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.

PubMed: 41982734
DOI: 10.1021/acsmedchemlett.5c00773

Experimental method

X-RAY DIFFRACTION (2.044 Å)