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

Airas, Justin; Bayas, Catherine A.; Ousidi, Abdellah N'ait; Itto, My Youssef Ait; Auhmani, Aziz; Loubidi, Mohammed; Esseffar, M.; Pollock, Julie A.; Parish, Carol A.

doi:10.1016/j.ejmcr.2022.100034

Cited by 2 publications

(1 citation statement)

References 83 publications

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“…Previous works have studied the behavior of novel and repurposed drugs as SARS-CoV-2 inhibitors targeting the spike protein (Br et al, 2020;Jaiswal and Kumar, 2020;Wang et al, 2022), RNA polymerase (El Hassab et al, 2020;Parvez et al, 2020;Elkarhat et al, 2022), or the main protease enzyme (Alnajjar et al, 2020;Teli et al, 2021;Airas et al, 2022). The RBD of the spike protein is an often-used target in order to inhibit its interaction with hACE2 receptors, thereby preventing viral infection.…”

Section: Introductionmentioning

confidence: 99%

Exploring the disruption of SARS-CoV-2 RBD binding to hACE2

Carter,

Airas,

Gladden

et al. 2023

Front. Chem.

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The COVID-19 pandemic was declared due to the spread of the novel coronavirus, SARS-CoV-2. Viral infection is caused by the interaction between the SARS-CoV-2 receptor binding domain (RBD) and the human ACE2 receptor (hACE2). Previous computational studies have identified repurposed small molecules that target the RBD, but very few have screened drugs in the RBD–hACE2 interface. When studies focus solely on the binding affinity between the drug and the RBD, they ignore the effect of hACE2, resulting in an incomplete analysis. We screened ACE inhibitors and previously identified SARS-CoV-2 inhibitors for binding to the RBD—hACE2 interface, and then conducted 500 ns of unrestrained molecular dynamics (MD) simulations of fosinopril, fosinoprilat, lisinopril, emodin, diquafosol, and physcion bound to the interface to assess the binding characteristics of these ligands. Based on MM-GBSA analysis, all six ligands bind favorably in the interface and inhibit the RBD–hACE2 interaction. However, when we repeat our simulation by first binding the drug to the RBD before interacting with hACE2, we find that fosinopril, fosinoprilat, and lisinopril result in a strongly interacting trimeric complex (RBD-drug-hACE2). Hydrogen bonding and pairwise decomposition analyses further suggest that fosinopril is the best RBD inhibitor. However, when lisinopril is bound, it stabilizes the trimeric complex and, therefore, is not an ideal potential drug candidate. Overall, these results reveal important atomistic interactions critical to the binding of the RBD to hACE2 and highlight the significance of including all protein partners in the evaluation of a potential drug candidate.

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Section: Introductionmentioning

confidence: 99%

Exploring the disruption of SARS-CoV-2 RBD binding to hACE2

Carter,

Airas,

Gladden

et al. 2023

Front. Chem.

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Ionic liquid‐supported copper‐catalyzed synthesis of 2H‐indazoles under microwave irradiation

Dasmahapatra,

Chanda,

Maiti

2024

Journal of Heterocyclic Chem

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Five‐membered indazoles are recognized as a special scaffold having a broad spectrum of pharmacological properties among other heterocyclic compounds. New methods must be developed for the effective synthesis of 2H‐indazole because of the exceptionally high biological activity of compounds containing a 2H‐indazole core. We present the ionic liquid‐supported copper‐catalyzed one‐pot synthesis of 2H‐indazoles under microwave irradiation, continuing our ongoing investigation of the potential uses of bioactive compounds produced in the lab. The use of microwave and ionic liquid‐supported catalyst makes this process greener and more highly energy efficient than the conventional reported methods. Overall, by forming consecutive C‐N and N‐N bonds with the help of an ionic liquid‐supported copper catalyst, we have developed a novel green one‐pot technique for the synthesis of the 2H‐indazole motifs in very high yield.

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

Cited by 2 publications

References 83 publications

Exploring the disruption of SARS-CoV-2 RBD binding to hACE2

Exploring the disruption of SARS-CoV-2 RBD binding to hACE2

Ionic liquid‐supported copper‐catalyzed synthesis of 2H‐indazoles under microwave irradiation

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