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.

The Immunomodulatory Effects of Active Ingredients From Nigella sativa in RAW264.7 Cells Through NF-κB/MAPK Signaling Pathways

“…Among several medicinal plants, N. sativa is regarded as one of the most valuable nutrient-dense herbs in human history, and numerous scientific investigations are underway to confirm its traditional use ( 42 ). At the same time, researchers found that N. sativa seeds can be utilized as nutritional supplements for COVID-19 patients as an adjuvant treatment, which set off an upsurge of research on N. sativa seeds ( 43 – 45 ).…”

The naturally‐derived alkaloids as a potential treatment for COVID‐19: A scoping review

“…Overall, 11 studies (25.58%) approached the spike glycoprotein as target protein, being the alkaloids analyzed the following: crambescidin 826, cryptospirolepine, deoxynortryptoquivaline, ergotamine, hyoscyamine, nicotine docking on soluble angiotensin‐converting enzyme II receptor in complex with spike (S) protein of Indian SARS‐CoV‐2 (sACE2‐INS1), nigellidine, norbolidine, pallidine, piperine and quinadoline B (Borquaye et al, 2020; El‐Demerdash et al, 2021; Firdiana et al, 2021; Gyebi et al, 2020; Ismail et al, 2021; Selvaa Kumar, Kumar, & Wei, 2020; Maiti, Banerjee, & Kanwar, 2021; Maiti, Banerjee, Nazmeen, Kanwar, & Das, 2020; Mao, Bie, Xu, Wang, & Gao, 2021; Ogunyemi et al, 2020; Skariyachan, Gopal, Muddebihalkar, & Uttarkar, 2021).…”

“…The alkaloids nicotine, nigellidine, norboldine, piperine, quinadoline A and trytoquivaline showed binding capacity to the angiotensin‐converting enzyme II (ACE2) (Firdiana et al, 2021; Ismail et al, 2021; Maiti et al, 2021; Maurya, Kumar, Prasad, Bhatt, & Saxena, 2020; Selvaa Kumar, Kumar, & Wei, 2020).…”

“…This herb is extensively employed traditional medicine like Ayurveda and Unani due to its extract safety, anti‐oxidant, anti‐bacterial, anti‐inflammatory, anti‐hypertensive activity and immunomodulatory effects. Therefore, this compound found in N. sativa has been associated with high energy binding with spike glycoprotein, NSP2, nucleocapsid N, ACE1, ACE2, AT1, AT2, in addition to having strong interactions with Mpro (Maiti et al, 2020, 2021). Renal and hepatic toxicities of the alkaloid nigellidine were evaluated in female Wistar rats, revealing no important safety concerns for the use of this substance (Maiti et al, 2020).…”

Pan-Cancer Analysis of Genomic and Prognostic Characteristics Associated With Coronavirus Disease 2019 Regulators

“…The spike protein (S protein) of SARS-CoV binds to cell surface ACE2 receptors (9). ACE1, homologous to the ACE2 gene, may be involved in the progression of diseases caused by several human coronaviruses (10,11). Transmembrane serine protease 2 (TMPRSS2), a member of the serine protease family, facilitates human coronavirus infections (SARS-CoV and SARS-CoV-2) via proteolytic cleavage of the ACE2 receptor, which promotes viral uptake and cleavage of coronavirus spike glycoproteins, activating glycoproteins for host cell entry (12)(13)(14).…”