7BQY

THE CRYSTAL STRUCTURE OF COVID-19 MAIN PROTEASE IN COMPLEX WITH AN INHIBITOR N3 at 1.7 angstrom

Summary for 7BQY

• Entry DOI: 10.2210/pdb7bqy/pdb
• Related PRD ID: PRD_002214
• Descriptor: 3C-like proteinase, N-[(5-METHYLISOXAZOL-3-YL)CARBONYL]ALANYL-L-VALYL-N~1~-((1R,2Z)-4-(BENZYLOXY)-4-OXO-1-{[(3R)-2-OXOPYRROLIDIN-3-YL]METHYL}BUT-2-ENYL)-L-LEUCINAMIDE (3 entities in total)
• Functional Keywords: protease, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV); More
• Total number of polymer chains: 2
• Total formula weight: 34506.34

Authors

Liu, X.,Zhang, B.,Jin, Z.,Yang, H.,Rao, Z. (deposition date: 2020-03-26, release date: 2020-04-22, Last modification date: 2024-10-09)

Primary citation

Jin, Z.,Du, X.,Xu, Y.,Deng, Y.,Liu, M.,Zhao, Y.,Zhang, B.,Li, X.,Zhang, L.,Peng, C.,Duan, Y.,Yu, J.,Wang, L.,Yang, K.,Liu, F.,Jiang, R.,Yang, X.,You, T.,Liu, X.,Yang, X.,Bai, F.,Liu, H.,Liu, X.,Guddat, L.W.,Xu, W.,Xiao, G.,Qin, C.,Shi, Z.,Jiang, H.,Rao, Z.,Yang, H.
Structure of Mprofrom SARS-CoV-2 and discovery of its inhibitors.
Nature, 582:289-293, 2020

PubMed Abstract: A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19). Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (M) of SARS-CoV-2: M is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-2. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of M of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of M. Six of these compounds inhibited M, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 μM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.

PubMed: 32272481
DOI: 10.1038/s41586-020-2223-y

Experimental method

X-RAY DIFFRACTION (1.7 Å)