7RM2
Room temperature X-ray structure of SARS-CoV-2 main protease (Mpro) in complex with Mcule-CSR-494190-S1
Summary for 7RM2
| Entry DOI | 10.2210/pdb7rm2/pdb |
| Related | 7RLS |
| Descriptor | 3C-like proteinase, 6-[4-(3,5-dichloro-4-methylphenyl)piperazine-1-carbonyl]pyrimidine-2,4(1H,3H)-dione (3 entities in total) |
| Functional Keywords | cysteine protease, inhibitor complex, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2) |
| Total number of polymer chains | 1 |
| Total formula weight | 34208.78 |
| Authors | Kovalevsky, A.,Kneller, D.W.,Coates, L. (deposition date: 2021-07-26, release date: 2021-11-10, Last modification date: 2023-10-18) |
| Primary citation | Kneller, D.W.,Li, H.,Galanie, S.,Phillips, G.,Labbe, A.,Weiss, K.L.,Zhang, Q.,Arnould, M.A.,Clyde, A.,Ma, H.,Ramanathan, A.,Jonsson, C.B.,Head, M.S.,Coates, L.,Louis, J.M.,Bonnesen, P.V.,Kovalevsky, A. Structural, Electronic, and Electrostatic Determinants for Inhibitor Binding to Subsites S1 and S2 in SARS-CoV-2 Main Protease. J.Med.Chem., 64:17366-17383, 2021 Cited by PubMed Abstract: Creating small-molecule antivirals specific for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins is crucial to battle coronavirus disease 2019 (COVID-19). SARS-CoV-2 main protease (M) is an established drug target for the design of protease inhibitors. We performed a structure-activity relationship (SAR) study of noncovalent compounds that bind in the enzyme's substrate-binding subsites S1 and S2, revealing structural, electronic, and electrostatic determinants of these sites. The study was guided by the X-ray/neutron structure of M complexed with Mcule-5948770040 (compound ), in which protonation states were directly visualized. Virtual reality-assisted structure analysis and small-molecule building were employed to generate analogues of . enzyme inhibition assays and room-temperature X-ray structures demonstrated the effect of chemical modifications on M inhibition, showing that (1) maintaining correct geometry of an inhibitor's P1 group is essential to preserve the hydrogen bond with the protonated His163; (2) a positively charged linker is preferred; and (3) subsite S2 prefers nonbulky modestly electronegative groups. PubMed: 34705466DOI: 10.1021/acs.jmedchem.1c01475 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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