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

• Published in: European journal of medicinal chemistry reports Vol. 4; p. 100034
• Main Authors: Airas, Justin, Bayas, Catherine A., N'Ait Ousidi, Abdellah, Ait Itto, Moulay Youssef, Auhmani, Aziz, Loubidi, Mohamed, Esseffar, M'hamed, Pollock, Julie A., Parish, Carol A.
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 01.04.2022; The Authors. Published by Elsevier Masson SAS; Elsevier
• Subjects: Binding assay; Coronavirus; COVID-19; Drug discovery; Indazole; Inhibitors; Molecular dynamics; MPro; Protease; SARS-CoV-2; Scaffold; Substrate; Thiazolyl; Thiazolyl-indazole; MPro; Indazole; Molecular dynamics; Binding assay; Scaffold; COVID-19; Substrate; Thiazolyl; SARS-CoV-2; Coronavirus; Inhibitors; Protease; Thiazolyl-indazole; Drug discovery
• ISSN: 2772-4174; 2772-4174
• DOI: 10.1016/j.ejmcr.2022.100034

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. [Display omitted]