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

Abstract

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.

Graphical abstract

Fig. 1

Nigellidine and nCov binding was presented. The spike glycoprotein of COVID 19 has two parts; the central cannel and flexible attachment site. Attachment site are normally remain unexposed. During attachment with ACE2 receptor it becomes exposed. Nigellidine bound at the hinge region which controls the flexibility of spike glycoprotein attachment site.

Fig. 2

Nigellidine and ACE2 binding was presented. Angiotensine usually bound to ACE2 at an internal channel. Nigellidine was also found to block that internal channel. Nigellidine was also found to block the entry pocket of Angiotensine within ACE2.

Fig. 3

Nigellidine ACE mono-meric binding. Nigellidine was usually bound to ACE1 at its internal channel and outer surface of the ACE1 also. The active site location of ACE1 was represented which interacted with D7 and S8. The involved common amino acids were also blocked by nigellidine like ALA332.

Fig. 4

Angiotensine interacted with AT1 at two different site 1 & 2. At site 1 specific amino acids involved in Angiotensine inding was reported (a). Same sites were occupied by nigellidine where amino acid ASP1281 was blocked by nigellidine at site 1 (b). According to autodock analysis, nigellidine bonded with TYR184 which may indirectly hamper the Angiotensin binding (c). Nigellidine also negatively influenced the PHE182- angiotensin binding (d).

Fig. 5

Angiotensine interacted with AT2 at two different sites 1 & 2. At site 1 specific amino acids involved in Angiotensine inding was reported (a). Same sites were occupied by nigellidine where amino acid ARG182 was blocked by nigellidine at site 1 (b). According to autodock analysis, nigellidine bonded with ARG182 which compete with the Angiotensin binding directly(c). Nigellidine also negatively influenced the LYS215-angiotensin binding.

Fig. 6

Common pattern of Angiotensin interaction to different Angiotensin receptors. AT1 and AT2 have 7 and ACE2 have 8 amino acid long Angiotensin where sequential diversity found at 4th (K/I) and 6th (A/I/F) position. ACE2 have extra amino acid D. Among AT1, AT2 and ACE2 angiotensin, ARG2 interacted with common ASP molecule to their receptors. TYR4 interacted commonly with TYR of AT2 and ACE2. HIS6 commonly interacted with ARG of AT1 and AT2.

Fig. 7

Summarization of angiotensin regulations and its physiological actions. Influences on these regulations i.e. via SARS CoV2 infection may impair the ACE2 functions and its expressions. As a result, angiotensin function becomes severely altered that cleats vaso-turbulence and massive endothelial dysfunctions resulting in multiple organ failure. Further, this impairment is highly increased in co-morbid like hypertensive, cardiac, renal and diabetic patients.