In silico Nigellidine (N. sativa) bind to viral spike/active-sites of ACE1/2, AT1/2 to prevent COVID-19 induced vaso-tumult/vascular-damage/comorbidity

Vascul Pharmacol. 2021 Jun;138:106856. doi: 10.1016/j.vph.2021.106856. Epub 2021 Mar 18.


COVID-19, a global-pandemic binds human-lung-ACE2. ACE2 causes vasodilatation. ACE2 works in balance with ACE1. The vaso-status maintains blood-pressure/vascular-health which is demolished in Covid-19 manifesting aldosterone/salt-deregulations/inflammations/endothelial-dysfunctions/hyper-hypo- tension, sepsis/hypovolemic-shock and vessel-thrombosis/coagulations. Here, nigellidine, an indazole-alkaloid was analyzed by molecular-docking for binding to different Angiotensin-binding-proteins (enzymes, ACE1(6en5)/ACE2(4aph)/receptors, AT1(6os1)/AT2(5xjm)) and COVID-19 spike-glycoprotein(6vsb). Nigellidine strongly binds to the spike-protein at the hinge-region/active-site-opening which may hamper proper-binding of nCoV2-ACE2 surface. Nigellidine effectively binds in the Angiotensin- II binding-site/entry-pocket (-7.54 kcal/mol, -211.76, Atomic-Contact-Energy; ACE-value) of ACE2 (Ki 8.68 and 8.3 μmol) in comparison to known-binder EGCG (-4.53) and Theaflavin-di-gallate (-2.85). Nigellidine showed strong-binding (Ki, 50.93 μmol/binding-energy -5.48 kcal/mol) to mono/multi-meric ACE1. Moreover, it binds Angiotensin-receptors, AT1/AT2 (Ki, 42.79/14.22 μmol, binding-energy, -5.96/-6.61 kcal/mol) at active-sites, respectively. This article reports the novel binding of nigellidine and subsequent blockage of angiotensin-binding proteins. The ACEs-blocking could restore Angiotensin-level, restrict vaso-turbulence in Covid patients and receptor-blocking might stop inflammatory/vascular impairment. Nigellidine may slowdown the vaso-fluctuations due to Angiotensin-deregulations in Covid patients. Angiotensin II-ACE2 binding (ACE-value -294.81) is more favorable than nigellidine-ACE2. Conversely, nigellidine-ACE1 binding-energy/Ki is lower than nigellidine-ACE2 values indicating a balanced-state between constriction-dilatation. Moreover, nigellidine binds to the viral-spike, closer-proximity to its ACE2 binding-domain. Taken together, Covid patients/elderly-patients, comorbid-patients (with hypertensive/diabetic/cardiac/renal-impairment, counting >80% of non-survivors) could be greatly benefited.

Keywords: Angiotensin receptors; COVID 19 treatment; Inhibitory constant; Nigellidine; Spike glycoproteins.

MeSH terms

  • Angiotensin-Converting Enzyme 2 / chemistry
  • Angiotensin-Converting Enzyme 2 / metabolism*
  • COVID-19 / metabolism*
  • COVID-19 / pathology
  • COVID-19 / prevention & control
  • Comorbidity
  • Computer Simulation / trends
  • Drug Evaluation, Preclinical / methods
  • Humans
  • Molecular Docking Simulation / methods
  • Nigella sativa*
  • Peptidyl-Dipeptidase A / chemistry
  • Peptidyl-Dipeptidase A / metabolism*
  • Plant Extracts / isolation & purification
  • Plant Extracts / metabolism*
  • Plant Extracts / therapeutic use
  • Protein Binding / physiology
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptor, Angiotensin, Type 1 / chemistry
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Receptor, Angiotensin, Type 2 / chemistry
  • Receptor, Angiotensin, Type 2 / metabolism*
  • SARS-CoV-2 / drug effects
  • SARS-CoV-2 / metabolism


  • Plant Extracts
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • ACE protein, human
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2