Design and synthesis of pyrazolone-based compounds as potent blockers of SARS-CoV-2 viral entry into the host cells.

Autor: Obakachi VA; Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa., Kushwaha ND; Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa., Kushwaha B; Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa., Mahlalela MC; Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa., Shinde SR; Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa., Kehinde I; School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban 4000, South Africa., Karpoormath R; Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa.
Jazyk: angličtina
Zdroj: Journal of molecular structure [J Mol Struct] 2021 Oct 05; Vol. 1241, pp. 130665. Date of Electronic Publication: 2021 May 13.
DOI: 10.1016/j.molstruc.2021.130665
Abstrakt: SARS-CoV-2 are enveloped positive-stranded RNA viruses that replicate in the cytoplasm. It relies on the fusion of their envelope with the host cell membrane to deliver their nucleocapsid into the host cell. The spike glycoprotein (S) mediates virus entry into cells via the human Angiotensin-converting enzyme 2 (hACE2) protein located on many cell types and tissues' outer surface. This study, therefore, aimed to design and synthesize novel pyrazolone-based compounds as potential inhibitors that would interrupt the interaction between the viral spike protein and the host cell receptor to prevent SARS-CoV 2 entrance into the cell. A series of pyrazolone compounds as potential SARS-CoV-2 inhibitors were designed and synthesized. Employing computational techniques, the inhibitory potentials of the designed compounds against both spike protein and hACE2 were evaluated. Results of the binding free energy from the in-silico analysis, showed that three compounds (7i, 7k and 8f) and six compounds (7b, 7h, 7k, 8d, 8g, and 8h) showed higher and better binding high affinity to SARS-CoV-2 Sgp and hACE-2, respectively compared to the standard drugs cefoperazone (CFZ) and MLN-4760. Furthermore, the outcome of the structural analysis of the two proteins upon binding of the inhibitors showed that the two proteins (SARS-CoV-2 Sgp and hACE-2) were stable, and the structural integrity of the proteins was not compromised. This study suggests pyrazolone-based compounds might be potent blockers of the viral entry into the host cells.
Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(© 2021 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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