The B.1.617.2 known as Delta-variant harbored diverse Spike-mutations. It is more transmissible than other (wild/D614G/N501Y) with developed immune-evasion mechanism. Currently, the binding-affinity of these variant spikes with human lung-ACE2 was evaluated aiming at some preventive/therapeutic strategies. Structure of spike-variants were retrieved from PDB/GISAID and used for homology-modeling (SWISS-MODEL). Different combination of spike-ACE2 binding 1:1 or competitive blind-docking was performed using Haddock2.4 web-server. After screening, two cut-segments (84 amino-acid of wild-spike, 432-516 Cut1 and Cut2, an in-silico desired-mutation T500S in Cut1) were tested (Swiss-model Expasy-server) as blocker/inhibitor of spike-variants (PyMOL-V2.2.2). Results explored the molecular-basis and energetic of Delta binding-affinity to ACE2 is far more than others. The numbers of H-bonding with their average-length, bonding-energy, Van-Der-Walls energy, Haddock-score were highly favorable for more stable-binding of Delta-RBD. The Ramachandran-plot (Zlab/UMassMed Bioinfo) data supports a post-binding stable structural-complex. The best Haddock scores of -120.8 +/- 2.6 were observed for Delta with Van-Der-Walls and electrostatic-energy of -62.9 and -208.7, respectively with highest binding-affinity (ΔG) of -10.7 kcal/mol. Its THR500 and GLN506 strongly bind with ACE2 LYS353. The Delta-ACE2 complex showed 5 H-bond (1.7Å-2.8Å) interactions. The Cut1 and its mutant T500S; Cut2 completely blocked Delta-spike binding to ACE2 with ΔG -8.4 and -10.6 kcal/mol, respectively. But during competition between 2 Cuts, Cut1 showed better results. Bioinformatics/molecular-modeling is an emerging field for screening of some drug/therapeutic targets from numerous options minimizing time and expenses. Present data unraveled the molecular-basis of higher affinity of Delta-spike to ACE2 and its therapeutic-strategies. Laboratory experimental outcome will help for further validation.

Background: In some breast cancers, decreased estrogen-sulfotransferase (SULT1E1) and its inactivation caused by oxidative-stress lead to elevated E2 levels as well as hypoxia-inducible tissue-damaging factors. Methods: Here, matrix-metalloproteases (MMP2/9) activity and SULT1E1-HIF1α protein/gene expression (Western-blot/RTPCR) were assessed in human breast-cancers versus their adjacent-tissues. Oxidant-stress neutralizer, chalcone (α,β unsaturated ketone) and SULT1E1-inducer dialyl-sulfide (source garlic; Allium sativum) were tested to prevent cancer causing factors in rat, in-vitro and in-vivo model. The antioxidant-enzymres SOD1, catalase, GPx and LDH, and matrix-degenerating MMP2/9 activities were assessed (gel-zymogram). Histoarchitecture (HE-staining) and tissue SULT1E1-localization (immuno-histochemistry) were screened. Extensive statistical-analysis were performed. Results: Human cancer-tissue expresses higher SULT1E1, paralleling HIF1α protein/mRNA owing to lower LDH activity. In addition, increase of MMP2/9 activities commenced tissue damage. However, chalcone and DAS significantly induced SULT1E1 gene/protein, and suppressed HIF1α expression, and MMP2/9 activities in rat tissues. Correlation of individual parameter statistics and group statistics of t-test suggest significant correlation of oxidative-stress (MDA) with SULT1E1 (p=0.006), HIF1α (p=0.006) protein-expression. The NPSH showed a negative correlation (p=0.001) with HIF1α, These two proteins and SULT1E1 mRNA expressions in human breast tumor were significantly higher (p<0.05) compared to the adjacent tissues. Pearson correlation data suggest, SULT1E1 is correlated with NPSH in different exposure groups. Conclusions: Breast cancers associate with SULT1E1, HIF1α and MMPs deregulations. Higher SULT1E1-protein in advanced cancer, remain inactive in oxidant oxidative environment and may be re-activated in chalcone induced reducing-state. Moreover, DAS induced SULT1E1 mRNA expression augments its protein increment. Synergistic drug-effects commenced HIF1α and MMPs suppression. Further studies are necessary.

COVID-19 is the global-pandemic targets human-lung-ACE2 that converts Angiotensin-II to (1-7) peptide causing vasodilatation. Vasoconstriction caused by Angiotensin-II is produced from Angiotensin-I by ACE1. The vaso-status maintains blood-pressure/vascular-health of the individuals which is demolished in Covid-19 infection manifesting aldosterone/salt-deregulations/inflammations/endothelial-dysfunctions/hyper-hypo- tension, sepsis/hypovolemic-shock and vessel-thrombosis/coagulations. These cause comorbidity patients. 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). Data suggest that nigellidine strongly binds to the spike-protein at the hinge-region/active-site-opening which may hamper proper-binding of nCoV2-ACE2 surface. Nigellidine strongly (-7.54 kcal/mol, -211.76, Atomic-Contact-Energy; ACE-value) binds (>known-binderEGCG; -4.53 and Theaflavin-di-gallate; -2.85) in the Angiotensin-II binding-site/entry-pocket at ACE2 with Ki 8.68 and 8.3 µmol. Further, Nigellidine showed strong-binding (best Ki, 50.93µmol/binding-energy -5.48 kcal/mol) to both mono- and multi-meric ACE1-forms. Moreover, this compound binds Angiotensin-receptors, AT1/AT2 (Ki, 42.79/14.22 µmol, binding-energy, -5.96/-6.61 kcal/mol) at active-sites, respectively. Here, we first-time report that nigellidine can block all angiotensin-binding proteins where, the Angiotensin-bonded amino acids were more or less similar/analogous and effectively blocked by nigellidine. The ACEs-blocking could restore Angiotensin-level and restrict vaso-turbulence in Covid-infected patients and receptor-blocking might stop inflammatory/vascular impairment. Further, nigellidine may slowdown the vaso-fluctuations due to Angiotensin deregulations in Covid-infected patients. Angiotensin II-ACE2 binding (ACE-value -294.81) is more favorable than nigellidine-ACE2. Contrarily, nigellidine-ACE1 binding-energy/Ki are lower than nigellidine-ACE2 values indicating a balanced-state between constriction-dilatation. It is also noticed that nigellidine binds to the viral-spike, closer proximity to its ACE2 binding-domain. Taken together, Covid-infected-patients/elderly-patients/comorbid-patients (with hypertensive/diabetic/cardiac/renal impairment, counting >90% of non-survivors) could be greatly benefited.