38LZ

Crystal structure of SARS-CoV-2 (Covid-19) Nsp3 macrodomain in complex with compound 12p

This is a non-PDB format compatible entry.

Summary for 38LZ

• Entry DOI: 10.2210/pdb38lz/pdb
• Related: 8GIA 9AZX
• Descriptor: Non-structural protein 3, N-{2-[({(3aR,4R,6R,6aR)-6-[(8R)-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl]-6-cyano-2,2-dimethyltetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl}methyl)amino]-2-oxoethyl}-5-(4-fluorobenzene-1-sulfonamido)pyridine-3-carboxamide, 3,6,9,12,15,18,21,24,27,30-decaoxadotriacontane-1,32-diol, ... (4 entities in total)
• Functional Keywords: macrodomain, sars-cov-2, inhibitor, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 38385.44

Authors

Wallace, S.D.,Fromme, J.C. (deposition date: 2026-09-02, release date: 2026-09-23)

Primary citation

Peng, K.,Chakraborty, S.,Wallace, S.D.,Noll, J.C.G.,Shang, J.,Lu, X.,Choi, A.,Whittaker, G.,Fromme, J.C.,Lin, H.
Development of GS-441524 derivatives as potent SARS-CoV-2 Mac1 inhibitors via a direct-to-biology approach.
Eur.J.Med.Chem., 320:119280-119280, 2026

PubMed Abstract: Targeting viral macrodomains (Mac) has emerged as a promising strategy for antiviral drug development, especially after the outbreak of COVID-19 that claimed millions of lives worldwide. Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mac1 inhibitors have been reported in the past few years. In the present work, we converted GS-441524 (IC of ∼10 μM for SARS-CoV-2 Mac1) to KP-S54 (18c), a potent inhibitor of both SARS-CoV-2 Mac1 (IC: 44 nM) and Middle East respiratory syndrome coronavirus (MERS-CoV) Mac1 (IC: 91 nM) through an iterative direct-to-biology approach. This approach leverages efficient amide-coupling reaction and the mix-and-read fluorescence polarization (FP) assays where reaction mixtures could be screened directly without purification. Cocrystal structure of a selected derivative (12p) binding to SARS-CoV-2 Mac1 revealed the binding mode, which will guide future drug development against viral macrodomains.

PubMed: 42721552
DOI: 10.1016/j.ejmech.2026.119280

Experimental method

X-RAY DIFFRACTION (1.53 Å)