Submission Details
Molecule(s):
NS(=O)(=O)c1ccccc1C(=O)NC[C@@H]1CCCO1
Design Rationale:
Rationale: The binding site of MPro_x1086 and MPro_x1187 connects two highly flexible termini regions of MPro. In other coronaviruses, e.g. SARS-CoV, these termini regions were shown to play an important role in protease activity and dimerization.(1,2) This idea here presented consists in merging these two fragments to explore distinct networks of hydrogen bonds and a pi-pi stacking with Phe8. A minimized complex with this new proposed ligand in MPro is available (attached). It shows hydrogen bonds with the backbone of Met6, T-shaped pi-pi interactions with Phe8 and a cation-pi interaction between the phenyl ring of the molecule and Arg298. This would provide a lead compound for Mpro inhibition, with significant room for ligand optimization. Methodology: An initial visual inspection identified the pocket of MPro_x1086 and MPro_x1187 among the very few outside of the protease activity pocket of MPro that is not fully solvent exposed, and therefore it provides room for ligand optimization. MPro_x1086 forms a unique hydrogen bond with the backbone of Met6, and its phenyl group forms a pi-pi interaction with Phe8. Furthermore, its –NH2 group is close enough to the side chain of Asp295, raising the possibility of additional H-bonds. MPro_x1187 also forms pi-pi stacking with Phe8, while its amide group is not very far from Asn299. Therefore, a hybrid molecule consisting of these two fragments was built, and further minimized in MPro. References: 1. https://jvi.asm.org/content/82/5/2515 2. https://www.ncbi.nlm.nih.gov/pubmed/18305043
Other Notes:
(a) I couldn't find fragment x1187 in the list of IDs, so I selected only x1086. But this is a proposal that merges two fragments. (b) This idea is just a first step towards a lead compound for MPro inhibition. There is room for ligand optimization, specially in two regions: (i) The non-aromatic 5-membered ring is mostly solvent exposed, and could be replaced for better PK properties, e.g. morpholine, piperidine,... (ii) A SAR around the aromatic ring could be performed aiming at improving the cation-pi interaction with Arg298.