Pyrazole, imidazole and triazole: In silico, docking and ADMET studies against SARS-CoV-2.

The Coronavirus pandemic, Covid-19 and SARS-Cov-2 put multidisciplinary research by chemists, biologists, pharmacists and theorists necessary and primordial task to find new active biomolecules which will be beneficial for all humanity. The azoles drugs are electronic rich, they should be used with caution, and an understanding of their pharmacokinetic profile, safety, absorption, distribution, excretion, metabolism, toxicity, and drug-drug interaction profiles is important to provide effective and cure therapy. In these objectives and goals, twenty aromatic nitrogen heterocycle compounds were chosen for in silico, docking and AMET studies against SARS-CoV-2. In this paper with respect to the protein S of SARS-CoV-2 properties, the GAUSSIAN 09w program used in the semi-empirical method at the AM1 level with the optimization of the geometry of the structures. Then Toxicity and physicochemical properties were evaluated by AMET. Molecular docking investigations conducted; the binding affinities as well as interactions of the sieve compounds with the SRAS-CoV-2 protein Spike using PyRx software. In general, the preliminary results are fructuous and needs further in vitro testes.

Synthesis and In Silico Study of Some New bis-[1,3,4]thiadiazolimines and bis-Thiazolimines as Potential Inhibitors for SARS-CoV-2 Main Protease.

A novel series of bis-[1,3,4]thiadiazolimines, and bis-thiazolimines, with alkyl linker, were synthesized through general routes from cyclization of 1,1'-(hexane-1,6-diyl)bis(3-phenylthiourea) and hydrazonoyl halides or α-haloketones, respectively. Docking studies were applied to test the binding affinity of the synthesized products against the Mpro of SARS-CoV-2. The best compound, 5h, has average binding energy (-7.50 ± 0.58 kcal/mol) better than that of the positive controls O6K and N3 (-7.36 ± 0.34 and -6.36 ± 0.31 kcal/mol). Additionally, the docking poses (H-bonds and hydrophobic contacts) of the tested compounds against the Mpro using the PLIP web server were analyzed.

An Insight Based on Computational Analysis of the Interaction between the Receptor-Binding Domain of the Omicron Variants and Human Angiotensin-Converting Enzyme 2.

Concerns have been raised about the high number of mutations in the spike protein of the new emergence of the highly transmissible Omicron variant (B.1.1529 lineage) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This variant's extraordinary ability to evade antibodies would significantly impair the current vaccination program. This present study aimed to computationally analyze the interaction between the receptor-binding domain (RBD) in the spike protein of Omicron variants and human angiotensin-converting enzyme 2 (hACE2). The docking results indicated that Omicron BA.2 has exceptionally strong interactions with hACE2 in comparison to Omicron BA.1, Delta, and wild-type, as indicated by various parameters such as salt bridge, hydrogen bond, and non-bonded interactions. The results of the molecular dynamics simulation study corroborate these findings, indicating that Omicron BA.2 has a strong and stable interaction with hACE2. This study provides insight into the development of an effective intervention against this variant.

An Insight Based on Computational Analysis of the Interaction between the Receptor-Binding Domain of the Omicron Variants and Human Angiotensin-Converting Enzyme 2

Concerns have been raised about the high number of mutations in the spike protein of the new emergence of the highly transmissible Omicron variant (B.1.1529 lineage) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This variant's extraordinary ability to evade antibodies would significantly impair the current vaccination program. This present study aimed to computationally analyze the interaction between the receptor-binding domain (RBD) in the spike protein of Omicron variants and human angiotensin-converting enzyme 2 (hACE2). The docking results indicated that Omicron BA.2 has exceptionally strong interactions with hACE2 in comparison to Omicron BA.1, Delta, and wild-type, as indicated by various parameters such as salt bridge, hydrogen bond, and non-bonded interactions. The results of the molecular dynamics simulation study corroborate these findings, indicating that Omicron BA.2 has a strong and stable interaction with hACE2. This study provides insight into the development of an effective intervention against this variant.

Corrigendum: Synthesis and Cytotoxic Activity of Novel Indole Derivatives and Their in silico Screening on Spike Glycoprotein of SARS-CoV-2.

[This corrects the article DOI: 10.3389/fmolb.2021.637989.].

Peptides-based therapeutics: Emerging potential therapeutic agents for COVID-19.

SARS-CoV-2 is a positive-sense RNA virus and it is the causative agent of the global COVID-19 outbreak. COVID-19 is similar to the previous outbreaks for instance SARS in 2002-2003 and MERS in 2012. As the peptides have many advantages, peptide-based therapeutics might be one of the possible ways in the development of COVID-19 specific drugs. SARS-CoV-2 enters into a human via its S protein by attaching with human hACE2 present on the cell membrane in the lungs and intestines of humans. hACE2 cleaves S protein into the S1 subunit for viral attachment and the S2 subunit for fusion with the host cell membrane. The fusion mechanism forms a six-helical bundle (6-HB) structure which finally fuses the viral envelope with the host cell membrane. hACE2 based peptides such as SBP1 and Spikeplug have shown their potential as antiviral agents. S protein-hACE2 interaction and the SARS-CoV-2 fusion machinery play a crucial part in human viral infection. It is evident that if these interactions could be blocked successfully and efficiently, it could be the way to find the drug for COVID-19. Several peptide-based inhibitors are potent inhibitors of S protein-hACE2 interaction. Similarly, the antiviral activity of the antimicrobial peptide, lactoferrin makes it an important candidate for the COVID-19 drug development process. A candidate drug, RhACE2-APN01 based on recombinant hACE2 peptide has already entered phase II clinical trials. This review sheds light on different aspects of the feasibility of using peptide-based therapeutics as the promising therapeutic route for COVID-19.

Current Perspectives in the Discovery of Newer Medications Against the Outbreak of COVID-19.

A rapid and increasing spread of COVID-19 pandemic disease has been perceived worldwide in 2020. The current COVID-19 disease outbreak is due to the spread of SARS-CoV-2. SARS-CoV-2 is a new strain of coronavirus that has spike protein on the envelope. The spike protein of the virus binds with the ACE-2 receptor of the human lungs surface for entering into the host. Therefore, the blocking of viral entry into the host by targeting the spike protein has been suggested to be a valid strategy to treat COVID-19. The patients of COVID-19 were found to be asymptomatic, cold, mild to severe respiratory illness, and leading to death. The severe illness has been noted mainly in old age people, cardiovascular disease patients, and respiratory disease patients. However, the long-term health effects due to COVID-19 are not yet known. Recently, the vaccines were authorized to protect from COVID-19. However, the researchers have put an effort to discover suitable targets and newer medications in the form of small molecules or peptides, based on in-silico methods and synthetic approaches. This manuscript describes the current perspectives of the causative agent, diagnostic procedure, therapeutic targets, treatment, clinical trials, and development of potential clinical candidates of COVID-19. The study will be useful to identify the potential newer medications for the treatment of COVID-19.

A novel nano therapeutic using convalescent plasma derived exosomal (CPExo) for COVID-19: A combined hyperactive immune modulation and diagnostics.

Extracellular vesicles like exosomes are important therapeutic tactics for treating COVID -19. By utilizing convalescent plasma derived exosomes (CPExo) from COVID-19 recovered persistence could accelerate the treatment strategies in the current state of affairs. Adequate literature has shown that administering the exosome to the in vivo system could be beneficial and could target the pathogens in an effective and precise manner. In this hypothesis we highlight the CPExo instead of convalescent plasma (CP), perhaps to dispense of exosomes are gratified and it's more effectively acquired immune response conferral through antibodies. COVID-19 convalescent plasma has billions of exosomes and it has aptitudes to carry molecular constituents like proteins, lipids, RNA and DNA, etc. Moreover, exosomes are capable of recognizing antigens with adequate sensitivity and specificity. Many of these derivatives could trigger an immune modulation into the cells and act as an epigenetic inheritor response to target pathogens through RNAs. COIVID-19 resistance activated plasma-derived exosomes are either responsible for the effects of plasma beyond the contained immune antibodies or could be inhibitory. The proposed hypothesis suggests that preselecting the plasma-derived antibodies and RNAs merged exosomes would be an optimized therapeutic tactic for COVID-19 patients. We suggest that, the CPExo has a multi-potential effect for treatment efficacy by acting as immunotherapeutic, drug carrier, and diagnostic target with noncoding genetic materials as a biomarker.

Inhibitory activities of bipyrazoles: a patent review.

INTRODUCTION: Bipyrazole is constituted from two pyrazole units either in their fully aromatic or partially hydrogenated forms. Pyrazoles are widely available in pharmaceutical and agrochemical products. Some pyrazoles are essential parts of commercial drugs in the market. This inspired us to collect the pharmacological activities of bipyrazoles that have potential therapeutic behaviors in several biological aspects but none of them were included in commercial drugs. AREAS COVERED: This review covers all biological and pharmacological potentials of bipyrazole derivatives during 2010-2021. The topics of this review comprised anticancer, antioxidant, anti-inflammatory, antimicrobial, antitubercular, antimalarial, insecticidal activities as well as enzymatic inhibitions. EXPERT OPINION: Bipyrazoles demonstrated a wide array of potent activities against various diseases such as anticancer, antitubercular, anti-inflammatory, and antimicrobial activities. Those are of great benefits for medicinal researchers to develop promising building blocks of bipyrazoles for treatment of diseases. The SAR studies showed that metallated bipyrazoles had better biological activities than bipyrazole ligands. For example, gold(III) and iridium(II) complexes of bipyrazoles were proved to be anticancer agents, and copper(I) as well as silver(I) complexes had excellent antibacterial activities. Several bipyrazoles were reported as antimalarial inhibitors better than chloroquine, the possible COVID-19 drug.

Green synthesis of silver nanoformulation of Scindapsus officinalis as potent anticancer and predicted anticovid alternative: Exploration via experimental and computational methods

The current study was focused on the investigation of anticancer activity of Scindapsus Officinalis fruit extract embedded silver nanoparticles (So-AgNPs) followed by anticovid activity prognosis of major phytocompounds, which participate in nanoformulation synthesis. The synthesis process involved the addition of AgNO3 solution (1 mM) and color change of the extract from light brown to dark, confirmed the formation of silver nanoparticles. Further, the characterization of synthesized So-AgNPs were done using different spectroscopical and microscopical techniques. FTIR spectra of So-AgNPs indicated vibrational peaks of polyphenolic hydroxyl groups, which are responsible for the stabilization of nanoformulation. Others microscopy methods such as SEM, TEM, XRD, and EDX illustrated that the synthesized So-AgNPs consist irregular size, spherical shape and thoroughly dispersed above the plane. Anticancer evaluation illustrated that the So-AgNPs have dose dependent anti-breast and anti-hepatic cancer activity (range of 97.72 ± 0.42 – 54.86 ± 0.46 % cell viability), which were noticed more effective than raw fruit extract of Scindapsus Officinalis. The computational anticovid prediction of major phyto-compound of the extract [which designate as inhibitor 1: ((2R,3S,4S,5R)-2-(hydroxymethyl)-6-(((1S,5S)-1-methyl-5-(2-methylprop-1-en-1-yl)cyclopent-2-en-1-yl)oxy)tetrahydro-2H-pyran-3,4,5-triol)] illustrated moderate tendency to interact with corona main protease enzyme (expected pIC > 6 μM). However, the molecular docking and dynamics studies showed that selected compounds have moderate tendency to interact human dihydrofolate reductase and topoisomerase 1 enzyme. The accomplished approach shows that So-AgNPs with adsorbed phytocompounds on its surface consist valuable experimentally proved anticancer potency and computationally predicted anticovid effect. Thus, the formulation can be used as an alternative to the covid infected cancer population.

Synthesis and Cytotoxic Activity of Novel Indole Derivatives and Their in silico Screening on Spike Glycoprotein of SARS-CoV-2.

This work investigated the interaction of indole with SARS-CoV-2. Indole is widely used as a medical material owing to its astounding biological activities. Indole and its derivatives belong to a significant category of heterocyclic compounds that have been used as a crucial component for several syntheses of medicine. A straightforward one-pot three-component synthesis of indole, coupled with Mannich base derivatives 1a-1j, was synthesized without a catalyst. The products were confirmed by IR, 1H-NMR, 13C-NMR, mass spectra, and elemental analysis. The indole derivatives were tested for cytotoxic activity, using three cancer cell lines and normal cell lines of Human embryonic kidney cell (HEK293), liver cell (LO2), and lung cell (MRC5) by MTT assay using doxorubicin as the standard drug. The result of cytotoxicity indole compound 1c (HepG2, LC50-0.9 µm, MCF-7, LC50-0.55 µm, HeLa, LC50-0.50 µm) was found to have high activity compared with other compounds used for the same purpose. The synthesized derivatives have revealed their safety by exhibiting significantly less cytotoxicity against the normal cell line (HEK-293), (LO2), and (MRC5) with IC50 > 100 µg/ml. Besides, we report an in silico study with spike glycoprotein (SARS-CoV-2-S). The selective molecules of compound 1c exhibited the highest docking score -2.808 (kcal/mol) compared to other compounds. This research work was successful in synthesizing a few compounds with potential as anticancer agents. Furthermore, we have tried to emphasize the anticipated role of indole scaffolds in designing and discovering the much-awaited anti-SARS CoV-2 therapy by exploring the research articles depicting indole moieties as targeting SARS CoV-2 coronavirus.