8H3E

Complex structure of a small molecule (SPC-14) bound SARS-CoV-2 spike protein, closed state

Summary for 8H3E

• Entry DOI: 10.2210/pdb8h3e/pdb
• EMDB information: 34465
• Descriptor: Spike glycoprotein,Fibritin, 7-(6-nitro-2,3-dihydroindol-1-yl)-7-oxidanylidene-heptanoic acid, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: sars-cov-2, spike protein, complex, small molecule, closed, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 3
• Total formula weight: 428252.14

Authors

Meng, F.,Wang, Q.,Xie, Y.,Ni, X.,Huang, N. (deposition date: 2022-10-08, release date: 2023-03-22, Last modification date: 2024-11-06)

Primary citation

Wang, Q.,Meng, F.,Xie, Y.,Wang, W.,Meng, Y.,Li, L.,Liu, T.,Qi, J.,Ni, X.,Zheng, S.,Huang, J.,Huang, N.
In Silico Discovery of Small Molecule Modulators Targeting the Achilles' Heel of SARS-CoV-2 Spike Protein.
Acs Cent.Sci., 9:252-265, 2023

PubMed Abstract: The spike protein of SARS-CoV-2 has been a promising target for developing vaccines and therapeutics due to its crucial role in the viral entry process. Previously reported cryogenic electron microscopy (cryo-EM) structures have revealed that free fatty acids (FFA) bind with SARS-CoV-2 spike protein, stabilizing its closed conformation and reducing its interaction with the host cell target in vitro. Inspired by these, we utilized a structure-based virtual screening approach against the conserved FFA-binding pocket to identify small molecule modulators of SARS-CoV-2 spike protein, which helped us identify six hits with micromolar binding affinities. Further evaluation of their commercially available and synthesized analogs enabled us to discover a series of compounds with better binding affinities and solubilities. Notably, our identified compounds exhibited similar binding affinities against the spike proteins of the prototypic SARS-CoV-2 and a currently circulating Omicron BA.4 variant. Furthermore, the cryo-EM structure of the compound SPC-14 bound spike revealed that SPC-14 could shift the conformational equilibrium of the spike protein toward the closed conformation, which is human ACE2 (hACE2) inaccessible. Our identified small molecule modulators targeting the conserved FFA-binding pocket could serve as the starting point for the future development of broad-spectrum COVID-19 intervention treatments.

PubMed: 36844485
DOI: 10.1021/acscentsci.2c01190

Experimental method

ELECTRON MICROSCOPY (3.06 Å)