9R5T

NSP14 IN COMPLEX WITH LIGAND TDI-016037-NX-1

This is a non-PDB format compatible entry.

Summary for 9R5T

• Entry DOI: 10.2210/pdb9r5t/pdb
• Descriptor: Guanine-N7 methyltransferase nsp14, ZINC ION, S-ADENOSYL-L-HOMOCYSTEINE, ... (10 entities in total)
• Functional Keywords: novel coronavirus, viral protein, proteros, proteros biostructures gmbh
• Biological source: Severe acute respiratory syndrome coronavirus
• Total number of polymer chains: 2
• Total formula weight: 123739.49

Authors

Steinbacher, S.,Meyer, C. (deposition date: 2025-05-09, release date: 2025-08-27, Last modification date: 2025-10-01)

Primary citation

Meyer, C.,Michino, M.,Huggins, D.J.,Garzia, A.,Davis, J.A.,Miller, M.W.,Liverton, N.,Hoffmann, H.H.,Glickman, J.F.,Nitsche, J.,Ganichkin, O.,Steinbacher, S.,Rice, C.M.,Meinke, P.T.,Tuschl, T.
Discovery of Novel Isofunctional SARS-CoV‐2 NSP14 RNA Cap Methyltransferase Inhibitors by Structure-Based Virtual Screening.
Acs Med.Chem.Lett., 16:1789-1797, 2025

PubMed Abstract: In early 2020, SARS-CoV-2 spread into a worldwide pandemic, causing more than 7 million deaths. Direct-acting antivirals (DAAs) complementing vaccines and mitigating severe disease in at-risk populations remain important. Here, we used a structure-based virtual screening (SBVS) workflow to identify new SAH-dependent inhibitors of the SARS-CoV-2 RNA cap methyltransferase NSP14. We virtually screened the Enamine and Sigma in-stock screening collections as well as the 3 orders of magnitude larger Enamine REAL make-on-demand compound library, which produced better docking scores and higher virtual hit rates. While biochemical testing of 145 in-stock library compounds yielded a single NSP14-specific inhibitor, 123 chemically synthesized Enamine REAL SBVS compounds contained 10 hits specifically inhibiting NSP14 with half-maximal inhibitory concentrations (IC) below 10 μM. The new compounds were chemically distinct in atomic composition from any NSP14 inhibitors previously identified by conventional biochemical high-throughput screening (HTS) and may serve as starting points to develop novel SARS-CoV-2 DAAs.

PubMed: 40959264
DOI: 10.1021/acsmedchemlett.5c00339

Experimental method

X-RAY DIFFRACTION (1.89 Å)