tetano
Editor, Senior Moderator
J Biomol Struct Dyn
. 2023 Jul 21;1-11.
doi: 10.1080/07391102.2023.2234031. Online ahead of print. Conformational perturbation of SARS-CoV-2 spike protein using N-acetyl cysteine: an exploration of probable mechanism of action to combat COVID-19
Utsab Debnath[SUP] 1 [/SUP], Amrita Mitra[SUP] 2 [/SUP], Varun Dewaker[SUP] 3 [/SUP], Yenamandra S Prabhakar[SUP] 3 [/SUP], Raghu Tadala[SUP] 4 [/SUP], Kiran Krishnan[SUP] 4 [/SUP], Padmakar Wagh[SUP] 4 [/SUP], Umashankar Velusamy[SUP] 4 [/SUP], Aastha Baliyan[SUP] 5 [/SUP], Anura V Kurpad[SUP] 6 [/SUP], Parthasarathi Bhattacharyya[SUP] 7 [/SUP], Amit Kumar Mandal[SUP] 5 [/SUP]
Affiliations
The infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) resulted in a pandemic with huge death toll and economic consequences. The virus attaches itself to the human epithelial cells through noncovalent bonding of its spike protein with the angiotensin-converting enzyme-2 (ACE2) receptor on the host cell. Based on in silico studies we hypothesized that perturbing the functionally active conformation of spike protein through the reduction of its solvent accessible disulfide bonds, thereby disintegrating its structural architecture, may be a feasible strategy to prevent infection by reducing the binding affinity towards ACE2 enzyme. Proteomics data showed that N-acetyl cysteine (NAC), an antioxidant and mucolytic agent been widely in use in clinical medicine, forms covalent conjugates with solvent accessible cysteine residues of spike protein that were disulfide bonded in the native state. Further, in silico analysis indicated that the presence of the selective covalent conjugation of NAC with Cys525 perturbed the stereo specific orientations of the interacting key residues of spike protein that resulted in threefold weakening in the binding affinity of spike protein with ACE2 receptor. Interestingly, almost all SARS-CoV-2 variants conserved cystine residues in the spike protein. Our finding results possibly provides a molecular basis for identifying NAC and/or its analogues for targeting Cys-525 of the viral spike protein as fusion inhibitor and exploring in vivo pharmaco-preventive and its therapeutic potential activity for COVID-19 disease. However, in-vitro assay and animal model-based experiment are required to validate the probable mechanism of action.Communicated by Ramaswamy H. Sarma.
Keywords: MD simulation; N-acetyl cysteine (NAC); SARS-CoV-2; angiotensin-converting enzyme 2 (ACE2); disulfide bonds; mass spectrometry; molecular docking; proteomics; spike protein.
. 2023 Jul 21;1-11.
doi: 10.1080/07391102.2023.2234031. Online ahead of print. Conformational perturbation of SARS-CoV-2 spike protein using N-acetyl cysteine: an exploration of probable mechanism of action to combat COVID-19
Utsab Debnath[SUP] 1 [/SUP], Amrita Mitra[SUP] 2 [/SUP], Varun Dewaker[SUP] 3 [/SUP], Yenamandra S Prabhakar[SUP] 3 [/SUP], Raghu Tadala[SUP] 4 [/SUP], Kiran Krishnan[SUP] 4 [/SUP], Padmakar Wagh[SUP] 4 [/SUP], Umashankar Velusamy[SUP] 4 [/SUP], Aastha Baliyan[SUP] 5 [/SUP], Anura V Kurpad[SUP] 6 [/SUP], Parthasarathi Bhattacharyya[SUP] 7 [/SUP], Amit Kumar Mandal[SUP] 5 [/SUP]
Affiliations
- PMID: 37477247
- DOI: 10.1080/07391102.2023.2234031
The infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) resulted in a pandemic with huge death toll and economic consequences. The virus attaches itself to the human epithelial cells through noncovalent bonding of its spike protein with the angiotensin-converting enzyme-2 (ACE2) receptor on the host cell. Based on in silico studies we hypothesized that perturbing the functionally active conformation of spike protein through the reduction of its solvent accessible disulfide bonds, thereby disintegrating its structural architecture, may be a feasible strategy to prevent infection by reducing the binding affinity towards ACE2 enzyme. Proteomics data showed that N-acetyl cysteine (NAC), an antioxidant and mucolytic agent been widely in use in clinical medicine, forms covalent conjugates with solvent accessible cysteine residues of spike protein that were disulfide bonded in the native state. Further, in silico analysis indicated that the presence of the selective covalent conjugation of NAC with Cys525 perturbed the stereo specific orientations of the interacting key residues of spike protein that resulted in threefold weakening in the binding affinity of spike protein with ACE2 receptor. Interestingly, almost all SARS-CoV-2 variants conserved cystine residues in the spike protein. Our finding results possibly provides a molecular basis for identifying NAC and/or its analogues for targeting Cys-525 of the viral spike protein as fusion inhibitor and exploring in vivo pharmaco-preventive and its therapeutic potential activity for COVID-19 disease. However, in-vitro assay and animal model-based experiment are required to validate the probable mechanism of action.Communicated by Ramaswamy H. Sarma.
Keywords: MD simulation; N-acetyl cysteine (NAC); SARS-CoV-2; angiotensin-converting enzyme 2 (ACE2); disulfide bonds; mass spectrometry; molecular docking; proteomics; spike protein.