Investigating novel thiazolyl-indazole derivatives as scaffolds for SARS-CoV-2 MPro inhibitors

European Journal of Medicinal Chemistry Reports

Julie A. Pollock¹  Justin Airas¹  Catherine A. Bayas¹  Carol A. Parish¹  M'hamed Esseffar²  Abdellah N'Ait Ousidi²  Moulay Youssef Ait Itto²  Aziz Auhmani²  Mohamed Loubidi² 

[1] Department of Chemistry, University of Richmond, Gottwald Center for the Sciences, Richmond, VA, 23173, USA;Département de Chimie, Faculté des Sciences Semlalia, Cadi Ayyad University, BP, 2390, Marrakech, Morocco;

关键词: SARS-CoV-2;    Coronavirus;    COVID-19;    MPro;    Protease;    Substrate;   

DOI  :  

来源: DOAJ

【 摘 要 】

COVID-19 is a global pandemic caused by infection with the SARS-CoV-2 virus. Remdesivir, a SARS-CoV-2 RNA polymerase inhibitor, is the only drug to have received widespread approval for treatment of COVID-19. The SARS-CoV-2 main protease enzyme (MPro), essential for viral replication and transcription, remains an active target in the search for new treatments. In this study, the ability of novel thiazolyl-indazole derivatives to inhibit MPro is evaluated. These compounds were synthesized via the heterocyclization of phenacyl bromide with (R)-carvone, (R)-pulegone and (R)-menthone thiosemicarbazones. The binding affinity and binding interactions of each compound were evaluated through Schrödinger Glide docking, AMBER molecular dynamics simulations, and MM-GBSA free energy estimation, and these results were compared with similar calculations of MPro binding various 5-mer substrates (VKLQA, VKLQS, VKLQG) and a previously identified MPro tight-binder X77. From these simulations, we can see that binding is driven by residue specific interactions such as π-stacking with His41, and S/π interactions with Met49 and Met165. The compounds were also experimentally evaluated in a MPro biochemical assay and the most potent compound containing a phenylthiazole moiety inhibited protease activity with an IC50 of 92.9 ​μM. This suggests that the phenylthiazole scaffold is a promising candidate for the development of future MPro inhibitors.

【 授权许可】

Unknown