7M91

CRYSTAL STRUCTURE OF THE SARS-COV-2(2019-NCOV) MAIN PROTEASE IN COMPLEX WITH COMPOUND 25

Summary for 7M91

• Entry DOI: 10.2210/pdb7m91/pdb
• Descriptor: 3C-like proteinase, 5-{3-[3-chloro-5-(3,3,3-trifluoropropoxy)phenyl]-2-oxo-2H-[1,3'-bipyridin]-5-yl}pyrimidine-2,4(1H,3H)-dione (3 entities in total)
• Functional Keywords: viral protein, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 1
• Total formula weight: 34330.39

Authors

Deshmukh, M.G.,Ippolito, J.A.,Zhang, C.H.,Jorgensen, W.L.,Anderson, K.S. (deposition date: 2021-03-30, release date: 2021-06-30, Last modification date: 2023-10-18)

Primary citation

Deshmukh, M.G.,Ippolito, J.A.,Zhang, C.H.,Stone, E.A.,Reilly, R.A.,Miller, S.J.,Jorgensen, W.L.,Anderson, K.S.
Structure-guided design of a perampanel-derived pharmacophore targeting the SARS-CoV-2 main protease.
Structure, 29:823-, 2021

PubMed Abstract: There is a clinical need for direct-acting antivirals targeting SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, to complement current therapeutic strategies. The main protease (M) is an attractive target for antiviral therapy. However, the vast majority of protease inhibitors described thus far are peptidomimetic and bind to the active-site cysteine via a covalent adduct, which is generally pharmacokinetically unfavorable. We have reported the optimization of an existing FDA-approved chemical scaffold, perampanel, to bind to and inhibit M noncovalently with ICs in the low-nanomolar range and ECs in the low-micromolar range. Here, we present nine crystal structures of M bound to a series of perampanel analogs, providing detailed structural insights into their mechanism of action and structure-activity relationship. These insights further reveal strategies for pursuing rational inhibitor design efforts in the context of considerable active-site flexibility and potential resistance mechanisms.

PubMed: 34161756
DOI: 10.1016/j.str.2021.06.002

Experimental method

X-RAY DIFFRACTION (1.95 Å)