5WKJ
Target information
- RCSB PDB
- 5WKJ
- Title
- 2.05 A resolution structure of MERS 3CL protease in complex with inhibitor GC376
- Method
- X-RAY DIFFRACTION
- Resolution
- 2.05
- Classification
- HYDROLASE/HYDROLASE INHIBITOR
- Organism
- Middle East respiratory syndrome-related coronavirus
- Protein
- Replicase polyprotein 1a (K9N638)
- Year
- 2017
- Publication Title
- Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element.
- Abstract
-
There are currently no approved vaccines or small molecule therapeutics available for the prophylaxis or treatment of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections. MERS-CoV 3CL protease is essential for viral replication; consequently, it is an attractive target that provides a potentially effective means of developing small molecule therapeutics for combatting MERS-CoV. We describe herein the structure-guided design and evaluation of a novel class of inhibitors of MERS-CoV 3CL protease that embody a piperidine moiety as a design element that is well-suited to exploiting favorable subsite binding interactions to attain optimal pharmacological activity and PK properties. The mechanism of action of the compounds and the structural determinants associated with binding were illuminated using X-ray crystallography.
- External Link
- RCSB PDB
Ligand information
- HET
- K36
- Chain ID
- A
- HET Number
- 404
- Molecular Formula
- C21H31N3O8S
- Structure
-
- IUPAC Name
- (1S,2S)-2-[[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid
- InChI
- InChI=1S/C21H31N3O8S/c1-13(2)10-16(24-21(28)32-12-14-6-4-3-5-7-14)19(26)23-17(20(27)33(29,30)31)11-15-8-9-22-18(15)25/h3-7,13,15-17,20,27H,8-12H2,1-2H3,(H,22,25)(H,23,26)(H,24,28)(H,29,30,31)/t15-,16-,17-,20-/m0/s1
- InChI Key
- BSPZFJDYQHDZNR-BOSXTWCSSA-N
- Canonical SMILES
- CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C[C@@H]1CCNC1=O)[C@@H](O)S(O)(=O)=O
- Bioactivity data
- CI006853
Covalent Binding
- Warhead
- Sulfonic acid
- Reaction Mechanism
- Nucleophilic Substitution
- Residue
- CYS : 148
- Residue Chain
- A
- Interactions
- Pharmacophore Model
Ligand information
- HET
- B1S
- Chain ID
- A
- HET Number
- 403
- Molecular Formula
- C21H31N3O8S
- Structure
-
- IUPAC Name
- (1R,2S)-2-[[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid
- InChI
- InChI=1S/C21H31N3O8S/c1-13(2)10-16(24-21(28)32-12-14-6-4-3-5-7-14)19(26)23-17(20(27)33(29,30)31)11-15-8-9-22-18(15)25/h3-7,13,15-17,20,27H,8-12H2,1-2H3,(H,22,25)(H,23,26)(H,24,28)(H,29,30,31)/t15-,16-,17-,20+/m0/s1
- InChI Key
- BSPZFJDYQHDZNR-OGNFBWPZSA-N
- Canonical SMILES
- CC(C)C[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)N[C@@H](C[C@@H]1CCNC1=O)[C@H](O)S(O)(=O)=O
- Bioactivity data
- CI006854
Covalent Binding
- Warhead
- Sulfonic acid
- Reaction Mechanism
- Nucleophilic Substitution
- Residue
- CYS : 148
- Residue Chain
- A
- Interactions
- Pharmacophore Model