Abstract: Preprint: Please note that this article has not completed peer review. Active-site Molecular docking of Nigellidine to nucleocapsid/Nsp2/Nsp3/MPro of COVID-19 and to human IL1R and TNFR1/2 may stop viralgrowth/cytokine-flood, and the drug source Nigella sativa (black cumin) seeds show potent antioxidant role in experimental rats. CURRENT STATUS: POSTED Smarajit Maiti Oriental Institute of Science and Technology, Midnapore, India maitism@rediffmail.comCorresponding Author ORCiD: https://orcid.org/0000-0002-1354-1303 Amrita Banerjee Oriental Institute of Science and Technology, Midnapore, India Aarifa Nazmeen Oriental Institute of Science and Technology, Midnapore, India Mehak Kanwar Oriental Institute of Science and Technology, Midnapore, India Shilpa Das Oriental Institute of Science and Technology, Midnapore, India 10.21203/rs.3.rs-26464/v1 SUBJECT AREAS Bioinformatics KEYWORDS SARS CoV 2 proteins, cytokine, Nigellidine, inhibition, molecular docking, cytotoxicity test, rat model. 1 Abstract The recent outbreak of SARS CoV-2 has changed the global scenario of human lives and economy. In this pandemic-outbreak the ratio of infected person is much higher than the death encountered. Most of the dead patients were observed with dysfunction/failure of cardiac and renal systems. Beside this a ‘cytokine storm’ namely TNF-α/IL1 receptors i.e. TNFR1/TNFR2/IL1R over-functioning was reported in the infected-persons. Here, nigellidine, an indazole-alkaloid and key-component of Nigella Sativa L. (NS); black-cumin-seed, has been analyzed for COVID-19 different protein and TNFα receptors TNFR1/TNFR2 and IL1R inhibition through molecular-docking study and biochemical-study of cuminseed extract exposure to experimental-rat. The NMR, X-ray-crystallographic or Electron-microscopic structures of COVID-19 Main-protease(6LU7), Spike-glycoprotein(6vsb), NSP2(QHD43415_2), Nterminus-protenase (QHD43415_3), Nucleocapsid(QHD43423) and Human IL1R (1itb), TNFR1 (1ncf), TNFR2 (3alq) from PDB were retrieved/analyzed for receptor-ligand interaction in normal condition. Then those structures were docked with nigellidine using Autodock-software and Patchdock-server. Where nigellidine showed highest binding-energy of -7.61 (kcal/mol) and ligand-efficiency value of (-0.35) forming bonds with amino acids THR943/LYS945/MET1556/ALA1557/PRO1558/ILE1559. Highest ACE-value of -356.72 was also observed for nigellidine N-terminal-protease interaction. Nigellidine also showed strong interaction with NSP2 (-6.28) and Mpro/3CLpro_Q (-6.38s). Nigellidine showed affinity to TNFR1 (-6.81), IL1R (-6.23) and TNFR2 (-5.16). In rat experiment 2-groups (vehicle and NS treated) of female Wistar-rats were taken for experiments. The NS treated tissue showed marked decline in ALP/SGPT/ SGOT/MDA level then the basal-levels. From the Western-blot or activity analysis it was observed that Nigellidine, the sulfuryl-group containing drug showed no impact on Phenol-catalyzing ASTIV or Steroid-catalyzing EST expressions/activities and thus have no influence in sulfation-mediated adverse metabolic-processes. Current-results concluded that Nigellidine has hepato/reno-protective; immunomodulatory/anti-inflammatory and antioxidant activities as well as it inhibits important proteins of COVID-19. With steps to further validation/checking nigellidine can be used in COVID-19 infection.