Synthesis, Characterization and in vitro Anticancer Studies of New Co(II), Ni(II), Cu(II) and Zn(II) Complexes of (E)-4-((Quinoline-8-ylimino)methyl)benzene-1,2,3-triol Ligand

Herein, a new tridentate (NNO) Schiff base ligand, (E)-4-[(quinoline-8-ylimino)methyl]benzene-1,2,3- triol derived from the condensation of 8-aminoquinoline with 2,3,4-trihydroxy benzaldehyde is reported. The ligand was complexed with certain metal ions like Co(II) (1), Ni(II) (2), Cu(II) (3), Zn(II) (4) and were characterized by various spectroscopic and analytical techniques such as FT-IR, UV-Vis, 1H NMR, 13C NMR, ESI-Mass, ESR, elemental analysis and magnetic susceptibility. Spectral data revealed octahedral geometry for cobalt(II), nickel(II), copper(II) complexes and tetrahedral geometry for zinc(II) complex. All the metal(II) complexes along with the Schiff base ligand were screened for their anticancer activities. The CT-DNA binding studies revealed high binding propensity for metal complexes with Kb values 1.50 × 104 M-1 for 1; 3.62 × 104 M-1 for 2; 2.53 × 104 M-1 for 3 and 1.8 × 104 M-1 for 4, respectively. Anticancer studies against A549 & MCF-7 demonstrated excellent antiproliferative activity with IC50 values in the range 17.62-48.82 μM. A standard drug cisplatin was employed to compare the activity of metal complexes. The complexes exhibited remarkable antitumour activity due to their high binding ability with DNA. It is interesting to observe that the complexes did not produce any cytotoxicity towards the normal cell lines.

Lead Identification for Severe Acute Respiratory Syndrome Coronavirus-2 Spike D614G Variant of COVID-19: A virtual Screening Process

COVID-19, a pandemic disease caused by single-stranded RNA virus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The structural spike (S) protein of SARS-CoV-2 plays a vital role in host cell entry, where the Angiotensin-Converting Enzyme-2 (ACE2) receptor of the human cell binds to the Receptor Binding Domain (RBD) region of the S1 domain and makes cell entry. The binding affinity of SARS-CoV-2-ACE2 is tenfold higher than the SARS-CoV-1-ACE2. Recent studies expose that the SARS-CoV-2 S D614G variant is highly infectious than D614 protein, also the D614G variant is highly stable than D614. So far, there is no effective viral-specific regimen for COVID-19. To overcome such problems, in our study, we have utilized the ZINC database to screen potent leads against the highly transmitting SARS-CoV-2 spike D614G protein, through a virtual screening procedure. We have applied three computational tools iGEMDOCK server, AutoDock version 4.2.6 and admetSAR to get active leads. The ZINC000150588351 (Elbasvir), ZINC000064540179 (Sofosbuvir analogue) and ZINC000137700912 (Sofosbuvir analogue) molecules have a greater binding affinity with the high binding energies of -8.22 kcal/mol, -8.13 kcal/mol and -7.64 kcal/mol respectively. The molecules ZINC000064540179 and ZINC000137700912 have high binding energy than their core molecule Sofosbuvir (ZINC100074252) of -4.06 kcal/mol. The ADMET prediction of these molecules reveals satisfactory human intestinal absorption and non-mutagenic property. Our results deliver valuable contributions to the design of inhibitors against COVID-19.

Virtual Screening of Phytochemicals Targeting the Main Protease and Spike Protein of SARS-CoV-2: An In silico Approach

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is an emerging virus responsible for the ongoing Coronavirus Disease 19 (COVID-19) pandemic. Despite the advent of COVID-19 vaccines, pandemic fatigue is still escalating as new SARS-CoV-2 variants emerge and vaccine shortages hit globally. Hence, drug repurposing remains an alternative strategy to combat SARS-CoV-2. For centuries, plants have served as natural reservoirs of pharmacologically active compounds with minimal cytotoxicity and promising antimicrobial and antiviral activities. In this light, the present study was undertaken to virtually screen 33 phytochemicals across various cultivars against the main protease (Mpro) and Spike (S) protein of SARS-CoV-2 using ADME analysis. 31 phytochemicals obeying Lipinski’s rules were subjected to molecular docking using AutoDock Vina. Docking scores were determined by selecting the best conformation of the protein-ligand complex that exhibited the highest affinity. The study identified withanone, licoflavone A, and silibinin to interact with the S protein at the hACE2-binding site with high binding energies. Similarly, myricitrin, withanone, naringenin, licoflavone A, and silibinin exhibited high binding affinities with the substrate-binding pocket of Mpro between the domains I and II. Interestingly, licoflavone A, silibinin, and withanone interacted with both Mpro and S proteins in silico. Further, drug-likeness studies indicated withanone to be the most readily bioavailable phytochemicals among the three shortlisted ligands. Therefore, phytochemicals can be regarded as potential leads for developing inhibitors against this mysterious virus. In vitro investigations are further warranted to prove their antiviral efficacy.

Icotinib, Almonertinib, and Olmutinib: A 2D Similarity/Docking-based Study to Predict the Potential Binding Modes and Interactions into EGFR

In the current study, a 2D similarity/docking-based study was used to predict the potential binding modes of icotinib, almonertinib, and olmutinib into EGFR. The similarity search of icotinib, almonertinib, and olmutinib against a database of 154 EGFR ligands revealed the highest similarity scores with erlotinib (0.9333), osimertinib (0.9487), and WZ4003 (0.8421), respectively. In addition, the results of the docking study of the three drugs into EGFR revealed high binding free energies (Gb = −6.32 to −8.42 kcal/mol) compared to the co-crystallized ligands (Gb = −7.03 to −8.07 kcal/mol). Analysis of the top-scoring poses of the three drugs was done to identify their potential binding modes. The distances between Cys797 in EGFR and the Michael acceptor sites in almonertinib and olmutinib were determined. In conclusion, the results could provide insights into the potential binding characteristics of the three drugs into EGFR which could help in the design of new more potent analogs.

Zingiber officinale: Ayurvedic Uses of the Plant and In Silico Binding Studies of Selected Phytochemicals With Mpro of SARS-CoV-2

Among the large number of plants that are part of the Ayurvedic system of medicine in India and Bangladesh, Zingiber officinale Roscoe (Zingiberaceae), or ginger in English, holds a special place and is often referred to as “Mahaushadha” (great medicine) and “Vishvabhesaja” (worldwide or universal herb) to signify its special status. The plant and particularly its rhizomes are used both in the raw and dry form for the relief of a multitude of disorders. Since a number of these disorders occur in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it was of interest to perform in silico studies (molecular docking) to evaluate the binding affinities of a number of constituents of Zingiber officinale with the 3C-like protease or main protease (Mpro) of SARS-CoV-2, which plays an essential role in the cleavage of viral polyproteins and subsequent viral replication. Our studies indicated that 2 of the compounds present in ginger, namely, chlorogenic acid and hesperidin, had high binding affinities for Mpro with predicted binding energies of −7.5 and −8.3 kcal/mol. The two-dimensional and three-dimensional interactions also showed that, while chlorogenic acid interacts with one of the His41 amino acids of the catalytic dyad of Mpro, hesperidin interacts with the other amino acid Cys145, which can account for their predicted high binding energies and, therefore, possibly can inhibit Mpro activity. Taken together, our findings indicate that ginger, besides alleviating the symptoms induced by SARS-CoV-2, may also play a role in inhibiting the virus.

Natural phytochemicals, Phenformin, and Docosahexaenoic acid (DHA) as a Novel Inhibitors of IL-6 and ACE2 receptors, a Therapeutic Strategy for targeting COVID-19 Cell Entry and Cytokine Storm. An insilico Approach

Cytokine storm syndrome (CSS) is a life-threatening consequence of inflammatory immunological illnesses; it can also occur with COVID-19 infection. CSS is characterized by a disruption in cytokine synthesis, including regulatory, pro-inflammatory and anti-inflammatory cytokines, resulting in pathologic stimulation of innate in addition to adaptive (Th17 and Th1 mediated) response. In the pathophysiology of CSS, interleukin-6 could play a key role. The significant role of IL-6 in COVID-19 pathogenesis was established in a wide variety of researches, which reported that the plasma concentration of IL-6 was raised in COVID-19 patients with severe symptoms. COVID-19 spike protein binding to angiotensin-converting enzyme 2 (ACE2), the virus's cellular receptor, causes a cascade of molecular processes that could result in hyperinflammation which may lead to cytokine storm. Therefore, the development of new natural therapies and repurposing some drugs such as Phenformin and Docosahexaenoic acid that could compete with COVID-19 for ACE2 binding or inhibit IL-6 activity may possibly help COVID-19 patients avoid a cytokine storm and save their lives through inhibiting IL-6 and preventing SARS-CoV-2 RBD attachment to ACE2. Herein we made a docking based screening for some natural phytochemicals and drugs that could be repurposed according to our findings to counter COVID-19 cell entry and inhibit the hyper activation of IL-6. Our results revealed that a five phytochemicals including Epigallocatechin gallate (EGCG), bromelain, luteolin, vitexin and isovitexin) showed a high binding affinities with best interactions with the active sites of IL-6. The binding affinities of these phytochemicals including, EGCG, bromelain, luteolin, vitexin and isovitexin with IL-6 were (-7.7, -6.7, -7.4, -7.2 and − 7.3 ), respectively. In addition to, phenformin showed a high binding affinity with best interactions with the active sites of IL-6 and ACE2. The binding affinity of phenformin with IL-6 was (-7.4) and with ACE 2 ( -7.2). Docosahexaenoic acid (DHA) had a moderate binding affinity and moderate interactions with the active sites of IL-6 and had a high binding affinity with best interactions with ACE2 active sites. The binding affinity of Docosahexaenoic acid(DHA) with IL-6 was (-5.3) and with AC2 (-6.3).ConclusionProposing possible IL-6 inhibitors with less adverse effects has been suggested as a way to aid COVID-19 patients who are suffering from severe cytokine storms. This study has been designed to elucidate the potential of potent antiviral phytocompounds as well as phenformin and Docosahexaenoic acid (DHA) as a potent ACE2 and IL-6 inhibitors. The compounds interact with different active sites of IL6 and ACE2 which are involved in direct or indirect contacts with the ACE2 and IL-6 receptors which might act as potential blockers of functional ACE2 and IL-6 receptor complex. It worth mentioning that phenformin which showed high binding affinity with both ACE2 and IL-6 is currently under investigation for treating COVID-19 ClinicalTrials.gov Identifier: NCT05003492