Secondary Structures of MERS-CoV, SARS-CoV, and SARS-CoV-2 Spike Proteins Revealed by Infrared Vibrational Spectroscopy.

All coronaviruses are characterized by spike glycoproteins whose S1 subunits contain the receptor binding domain (RBD). The RBD anchors the virus to the host cellular membrane to regulate the virus transmissibility and infectious process. Although the protein/receptor interaction mainly depends on the spike's conformation, particularly on its S1 unit, their secondary structures are poorly known. In this paper, the S1 conformation was investigated for MERS-CoV, SARS-CoV, and SARS-CoV-2 at serological pH by measuring their Amide I infrared absorption bands. The SARS-CoV-2 S1 secondary structure revealed a strong difference compared to those of MERS-CoV and SARS-CoV, with a significant presence of extended ß-sheets. Furthermore, the conformation of the SARS-CoV-2 S1 showed a significant change by moving from serological pH to mild acidic and alkaline pH conditions. Both results suggest the capability of infrared spectroscopy to follow the secondary structure adaptation of the SARS-CoV-2 S1 to different environments.

Alternative structures of RNA control gene expression and offer therapeutic strategies

RNA viruses are diverse and abundant pathogens responsible for numerous human ailments, from common colds to AIDS, SARS, Ebola, and other dangerous diseases. RNA viruses possess relatively compact genomes and have therefore evolved multiple mechanisms to maximize their coding capacities, often using overlapping reading frames. In this way, one RNA sequence can encode multiple proteins via mechanisms including alternative splicing and ribosomal frameshifting. Many such processes in gene expression involve the RNA folding into three-dimensional structures that can recruit ribosomes without initiation factors, hijack host proteins, cause ribosomes to frameshift, and expose or occlude regulatory protein binding motifs to ultimately control each key process in the viral life cycle. I will discuss the RNA structure of HIV-1 and SARS-CoV-2 and the importance of alternative conformations assumed by the same RNA sequence in controlling gene expression of viruses and bacteria.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.

VHH DIMER P559-R45L NEUTRALIZES SARS-CoV-2 BY STABILIZING SPIKE IN UP CONFORMATION

Background: SARS-CoV-2 Omicron subvariants are highly resistant to vaccineinduced immunity and therapeutic monoclonal antibodies. We previously reported anti-SARS-CoV-2 spike alpaca nanobodies (VHHs) P86 and P17 that potently neutralize the wild type and VOCs from Alpha to Omicron BA.1 and BA.2, but not Omicron subvariants after that such as BA.4/5. Thus, we tried to establish a new VHH that can neutralize all the variants including BA.4/5. Method(s): We developed VHH trimers and heterodimers based on the structural and computational analysis of Delta spike-immunized alpaca VHH library. We tested representative VHHs against SARS-CoV-2 spike by pseudovirus assays and generated VHH heterodimers. We further obtained Cryo-EM structure of Spike trimer and VHH monomer or heterodimer. Result(s): First, we generated series of P86 mutants to counteract L452R mutation in Delta or Omicron BA.5 subvariants and found that P86 R45L was most potent against D614G with an IC50 of 0.03 mug/mL. From the Delta spike-immunized VHH library, we also identified that homo-trimer of a new clone P559 neutralized SARS-CoV-2 Delta and Omicron BA.5 variants with an IC50 of 0.077 and 0.54 mug/mL, respectively. We finally generated P559-R45L heterodimer that neutralized all the variants so far including Omicron BA.5 with an IC50 of 0.39 mug/mL. Cryo-EM structure revealed that three molecules of P559- R45L heterodimer bridged two RBD molecules in the spike trimer and stabilized spike timers with RBD in the up conformation. Conclusion(s): We developed VHH P559-R45L heterodimer that potently neutralized all the variants including Omicron subvariants through unique structural interaction.

Study on Molecular Docking of 'Nucleocapsid (N) Protein of Sars-Cov-2' and 'Mcf-7'

The process of eliminating viral infection and massive control from spreading furthermore by any variants may lead to a pandemic in the near future. On the other aspect, the impact of eradicating by the initial stage to prevent, treat carcinoma to decline the affected and death rate to maximum amount by Molecular Docking. The quickest and easiest method to search out the potential drugs is by analyzing the ligand-protein interactions compared to the traditional ways. Drugs of antivirals and anti-cancer drugs are given for treating viral infections and cancers. Massive kinds of viruses affect humans with several diseases, from self-curable diseases to acute mortal diseases. In cancer, the diseases are known by the cells within humans;multiplication occurs and forming the tumors of malignant cells with the flexibility to be a pathological process. Herbal medicines are known to play enormous role by giving initial priority. Various plant species are being employed to cure or prevent viral infections and cancers. Molecular docking provides a fast understanding of the ligand's exploration of conformations, poses among drug targets' binding sites, and predicts the binding affinity of protein-ligand. Its main approach is to spot top-ranked conformations on compounds and means of docking to the active site of target of interest. Intake of naturally suggested fruits and vegetables leads to the goal of decreasing the death rate, and the count of females who are liable to breast cancers.Copyright All © 2023 are reserved by International Journal of Pharmaceutical Sciences and Research.

Corticosteroids hypersensitivity, looking for an ace up one's sleeve

Background: Although hypersensitivity reactions to corticosteroids are rare in the general population, they are not uncommon in high-risk patients who receive repeated doses of them. It is known that delayed reactions are more common than immediate ones. Atopic dermatitis is a risk factor for the development of allergic contact dermatitis from topical corticosteroids. Patients can also develop hypersensitivity reactions to nasal, inhaled, oral and parenteral corticosteroids. Method(s): We reported one case of a 72-year- old man with history of chronic obstructive pulmonary disease (GOLD 4) and atopic dermatitis, who experienced a morbilliform rash after intravenous hydrocortisone administration during his hospital admission for SARS-COV- 2 infection. Since 1995 he had experienced several late skin reactions with corticosteroids and after performing an allergy study he was diagnosed of delayed hypersensitivity to corticosteroids with good tolerance for intravenous hydrocortisone and inhaled mometasone. Closed patch tests were performed with hydrocortisone with immediate and late lectures of 48-96 hours. We also performed a controlled intravenous challenge with hydrocortisone (200 mg) as well as an oral challenge with deflazacort (30 mg) under surveillance in the intensive care unit. Result(s): Patch tests were negative and intravenous hydrocortisone challenge went positive after 48 hours with the same previous skin reaction. Our patient showed a good tolerance to deflazacort. Conclusion(s): Choosing an alternative corticosteroid is pivotal to the patient's safety and also decreases the worry of developing an allergic reaction. This evaluation becomes especially important in high-risk groups where steroids are a life-saving treatment. Baeck et al. classified corticosteroids according to their chemical structure, improving treatment options and recommendations that can be prescribed. Nevertheless, discordance continues to be observed between the results of patch tests and the patient's tolerance to various commercial preparations. In order to provide alternative treatments, it is advisable to perform exposure tests with corticosteroids from a group other than the one the patient is sensitized to. Deflazacort could be an alternative in emergency cases. (Figure Presented).

Molecular Docking and Dynamics of Phytochemicals From Chinese Herbs With SARS-CoV-2 RdRp

The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is causing coronavirus disease 2019 (COVID-19) pandemic. Ancient Chinese herbal formulas are effective for diseases caused by viral infection, and their effects on COVID-19 are currently being examined. To directly evaluate the role of Chinese herbs in inhibiting replication of SARS-CoV-2, we investigated how the phytochemicals from Chinese herbs interact with the viral RNA-dependent RNA polymerase (RdRP). Total 1025 compounds were screened, and then 181compounds were selected for molecular docking analysis. Four phytochemicals licorice glycoside E, diisooctyl phthalate, (-)-medicocarpin, and glycyroside showed good binding affinity with RdRp. The best complex licorice glycoside E/RdRp forms 3 hydrogen bonds, 4 hydrophobic interactions, 1 pair of Pi-cation/stacking, and 4 salt bridges. Furthermore, docking complexes licorice glycoside E/RdRp and diisooctyl phthalate/RdRp were optimized by molecular dynamics simulation to obtain the stable conformation. These studies indicate that they are promising as antivirals against SARS-CoV-2.Copyright © The Author(s) 2022.

Highly Twisted Conformation Thiopyrylium Photosensitizers for In Vivo Near Infrared‐II Imaging and Rapid Inactivation of Coronavirus

Despite significant effort, a majority of heavy‐atom‐free photosensitizers have short excitation wavelengths, thereby hampering their biomedical applications. Here, we present a facile approach for developing efficient near‐infrared (NIR) heavy‐atom‐free photosensitizers. Based on a series of thiopyrylium‐based NIR‐II (1000–1700 nm) dyads, we found that the star dyad HD with a sterically bulky and electron‐rich moiety exhibited configuration torsion and significantly enhanced intersystem crossing (ISC) compared to the parent dyad. The electron excitation characteristics of HD changed from local excitation (LE) to charge transfer (CT)‐domain, contributing to a ≈6‐fold reduction in energy gap (ΔEST), a ≈10‐fold accelerated ISC process, and a ≈31.49‐fold elevated reactive oxygen species (ROS) quantum yield. The optimized SP@HD‐PEG2K lung‐targeting dots enabled real‐time NIR‐II lung imaging, which precisely guided rapid pulmonary coronavirus inactivation.

Computational Docking Study of the Phytochemical Constituent, Silybin (Silybum marianum) against SARS-CoV-2 Omicron Variant Spike Glycoprotein: An In-silico Approach

SARS-CoV-2 is continually evolving with the emergence of new variants with increased viral pathogenicity. The emergence of heavily mutated Omicron (B.1.1.529) with spike protein mutations are known to mediate its higher transmissibility and immune escape that has brought newer challenges for global public health to contain SARS-CoV-2 infection. One has to come up with a therapeutic strategy against the virus so as to effectively contain the infection and spread. Natural phytochemicals are being considered a significant source of bioactive compounds possessing an antiviral therapeutic potential. Being a promising anticancer and chemo-preventive agent, Silybin holds a significant potential to be used as a therapeutic. In the present study, molecular docking of Silybin with Omicron spike protein (7QNW) was carried out. Molecular docking results showed greater stability of Silybin in the active site of the Omicron spike protein with suitable binding mode of interactions. The study reveals that Silybin has the potential to block the host ACE2 receptor-viral spike protein binding;thereby inhibiting the viral entry to human cells. Therefore, Silybin may be further developed as a medication with the ability to effectively combat SARS-CoV-2 Omicron.Copyright © The Author(s) 2023.

Studying the Predictive Effects of Bacterial Carotenoids in the Treatment of Endometriosis Using Virtual Screening Methods

Background: Endometriosis is a chronic inflammatory disease defined as the presence of endometrial tissue outside the uterus, which causes pelvic pain and infertility. Cytokines appear to play vital roles in the development and progression of endometriosis and associated infertility. Tumor necrosis factoralpha (TNF-alpha) is a multifunctional pro-inflammatory cytokine, responsible for autoimmune and inflammatory disorders. TNF- alpha plays an important role in endometrial physiology as well as during early implantation. In addition, this cytokine has a considerable pathophysiological function in diseases such as menorrhagia, endometriosis, or infertility due to its regulatory impact on proliferation, differentiation, and angiogenesis in the human endometrium. In women with endometriosis, TNF-alpha levels increases in peritoneal fluid and serum significantly. In the present study, we focused on finding novel small molecules that can directly block TNFalpha- hTNFR1 (human TNF receptor 1) interaction. Method(s): In this regard, TNF-alpha inhibiting capacity of natural carotenoids was investigated in terms of blocking TNF-alpha-hTNFR1 interaction with the help of a combination of in silico approaches, based on virtual screening, molecular docking, and molecular dynamics (MD) simulation. Result(s): A total of 125 carotenoids were selected out of 1204 natural molecules, based on their pharmacokinetics properties, and they all met Lipinski's rule of five. Among them, sorgomol, strigol, and orobanchol had the most favorable DELTAG with the best pharmacokinetics properties and were selected for MD simulation studies, which explored the complex stability and the impact of ligands on protein conformation. It was shown that sorgomol formed the most hydrogen bonds, resulting in the highest binding energy with the lowest RMSD and RMSF. Conclusion(s): Our results showed that sorgomol was the most appropriate candidate as a TNF-alpha inhibitor. In conclusion, the present study could serve to expand possibilities to develop new therapeutic small molecules against TNF-alpha which plays an important role in the inflammation of endometriosis.

Missense Variants of von Willebrand Factor in the Background of COVID-19 Associated Coagulopathy.

COVID-19 associated coagulopathy (CAC), characterized by endothelial dysfunction and hypercoagulability, evokes pulmonary immunothrombosis in advanced COVID-19 cases. Elevated von Willebrand factor (vWF) levels and reduced activities of the ADAMTS13 protease are common in CAC. Here, we aimed to determine whether common genetic variants of these proteins might be associated with COVID-19 severity and hemostatic parameters. A set of single nucleotide polymorphisms (SNPs) in the vWF (rs216311, rs216321, rs1063856, rs1800378, rs1800383) and ADAMTS13 genes (rs2301612, rs28729234, rs34024143) were genotyped in 72 COVID-19 patients. Cross-sectional cohort analysis revealed no association of any polymorphism with disease severity. On the other hand, analysis of variance (ANOVA) uncovered associations with the following clinical parameters: (1) the rs216311 T allele with enhanced INR (international normalized ratio); (2) the rs1800383 C allele with elevated fibrinogen levels; and (3) the rs1063856 C allele with increased red blood cell count, hemoglobin, and creatinine levels. No association could be observed between the phenotypic data and the polymorphisms in the ADAMTS13 gene. Importantly, in silico protein conformational analysis predicted that these missense variants would display global conformational alterations, which might affect the stability and plasma levels of vWF. Our results imply that missense vWF variants might modulate the thrombotic risk in COVID-19.

Molecular Docking and the Pharmacokinetic Properties of the Anti-Viral Compounds Towards SARS-CoV- An In-silico Approach

The main aim of this study is to determine the bioactive compounds which have drug-like properties and has the potential to combat the spike-glycoprotein of SARS-CoV-2. The 6LXT protein of covid-19 was chosen from the protein data bank as a target protein. The compounds which are potentially capable to bind with the target were picked from the PubChem database and docked using the tool Autodock 4.2. Molecular docking of the molecules was done with the best conformations of the ligands and grid size was selected according to the hit compounds' interaction with the target protein. The ligand binding sites with the target molecules were predicted using MetaPocket 2.0. The docking Score of 50 compounds wascarried out and also toxicity studies were carried out. The compounds selected were calculated to identify the best conformations having drug-likeness properties. The top 10 compounds were chosen for the structure-activity relationship based on their binding interactions with the protein and ligand. The ligands then underwent the pharmacokinetic analysis followed by Lipinski's and all the results were finalized and categorized. ManzamineA, Imatinib, and basotinib were elected as the peak compounds with the binding energy -9.01kcal/mol, -8.71kcal/mol, and -8.01kcal/mol.

Characterization of SARS-CoV-2 Isolate (MZ558159) for in Silico Drug Designing, Reported from India

Introduction: Inadequate information available about the genomics and proteomics characterization of SARS-CoV-2 isolates reported from India and other part of the globe. This characterization is important for the in silico drug designing as there are no approved medications available to treat SARS-CoV-2 infection. Aim(s): The aim of the present study is characterization of SARS-CoV-2 (MZ558159) isolate reported from India using homology modelling, validation and in silico drug designing methods. Material(s) and Method(s): Genome sequence of SARS-CoV-2 (MZ558159) was retrieved from NCBI, and four protein sequences selected for the homology modeling, validation and in silico drug designing e.g., QXN18496, QXN18498, QXN18504, and QXN18497. SWISS-MODEL and UCLA-DOE server used for homology modeling. Validation for structure model performed using PROCHECK and molecular docking using MCULE-1-Click server. Result(s): The surface glycoprotein (QXN18496) model corresponding to probability conformation with 93.6%, envelope protein (QXN18498) with 88.9%, nucleocapsid phosphoprotein (QXN18504) with 93.6%, and ORF3a protein (QXN18497) with 91.8% residues in core section of o-o plot that specifies accuracy of prediction model. The corresponding ProSA Z-score score -12.67, -0.01, -4.4, and -2.87 indicates the good quality of the models. Molecular dynamic simulation and docking studies revealed the inhibitor binds effectively at the SARS-CoV-2 (MZ558159) proteins. Predicted inhibitor 2-acetamido-2-deoxy-beta-D-glucopyranose exhibited effective binding affinity against surface glycoprotein (QXN18496). Conclusion(s):The results of study establish inhibitor 2-Acetamido-2-deoxy-beta-D-glucopyranose as valuable lead molecule with great potential for surface glycoprotein (QXN18496).

Wavelet-based Spectral Analysis For Protein Conformation Selection and Prediction Using AI in Drug Discovery Applications

Contemporary drug discovery relies heavily on massive high performance computing (HPC) resources from docking and molecular dynamics simulations of proteins interacting with drug candidate ligands, such as recently published form simulations on ORNL's SUMMIT in covid19 pharmaceutical research. This work presents a unique spectral analysis approach using wavelet transform (WT) to understand the correlation between the time evolution of protein conformations generated by molecular dynamics and specific protein conformations that are selected for binding by ligands. A DWT-based spectral analysis is performed on the unique protein descriptors previously identified to be important in protein: ligand binding. The new protein time-series information from the wavelet-based time-frequency domain analysis is used for a more refined protein conformation selection and improve the deep learning and machine learning (AI/ML) prediction framework to improve the prediction of binding vs. non-binding protein conformations for three target proteins ADORA2A, OPRD1 and OPRK1. In this work, wavelets are used for spectral analysis for their added benefit of simultaneous time-frequency resolution and denoising properties. © 2022 IEEE.

Phyllanthus tenellus Roxb. And Kaempferia parviflora Wall. ex Baker compounds as inhibitors of SARS-CoV-2 main protease and RNA-dependent RNA polymerase: A molecular docking study

Context: The outbreak of a novel coronavirus, SARS-CoV-2 has caused an unprecedented COVID-19 pandemic. To put an end to this pandemic, effective antivirals should be identified or developed for COVID-19 treatment. However, specific and effective antivirals or inhibitors against SARS-CoV-2 are still lacking. Aim(s): To evaluate bioactive compounds from Phyllanthus tenellus and Kaempferia parviflora as inhibitors against two essential SARS-CoV-2 proteins, main protease (Mpro) and RNA-dependent RNA polymerase (RdRp), through molecular docking studies and to predict the drug-likeness properties of the compounds. Method(s): The inhibition potential and interaction of P. tenellus and K. parviflora compounds against Mpro and RdRp were assessed through molecular docking. The drug-likeness properties of the compounds were predicted using SwissADME and AdmetSAR tools. Result(s): Rutin and ellagic acid glucoside from P. tenellus and 4-hydroxy-6-methoxyflavone and 5-hydroxy-3,7,4'-trimethoxyflavone from K. parviflora exhibited the highest binding conformations to Mpro by interacting with its substrate binding site that was predicted to halt the Mpro activity. As for RdRp, ellagitannin and rutin from P. tenellus and peonidin and 5,3'-dihydroxy-3,7,4'-trimethoxyflavone from K. parviflora were the best-docked compounds that bound to the RdRp catalytic domain (Asp760 and Asp761) and NTP-entry channel that were anticipated to stop RNA polymerization. However, in the context of drug developability, 4-hydroxy-6-methoxyflavone, 5-hydroxy-3,7,4'-trimethoxyflavone, peonidin and 5,3'-dihydroxy-3,7,4'-trimethoxyflavone from K. parviflora were highly potential to be oral active drugs compared to rutin, ellagic acid glucoside and ellagitannin from P. tenellus. Conclusion(s): P. tenellus and K. parviflora compounds, particularly the aforementioned compounds, were suggested as potential inhibitors of SARS-CoV-2 Mpro and RdRp. Copyright © 2022 Journal of Pharmacy & Pharmacognosy Research.

Computational Method on Hydroxychloroquine and Azithromycin for SARS-CoV-2: Binding Affinity Studies

World is facing a new pandemic called covid-19SARS-CoV-2) since a year ago. Unfortunately there is no treatment for Covid 19 nowadays as well as no potential therapies has been developed to overcome from coronavirus pandemic. Some potential drug molecules with combination have ability to respond for covid19 virus. From the research it was found that the reduction of viral load can be treated with hydroxychloroquine and azithromycin combination. We evaluate the mode of interactions of hydroxychloroquine and azithromycin with the dynamic site of SARS-CoV-2 coronavirus main protease. Molecular Structure-based computational approach viz. molecular docking simulations were performed to scale up their affinity and binding fitness of the docked complex of novel SARS-CoV-2 coronavirus protease and hydroxychloroquine and azithromycin. The natural inhibitor N3 of novel SARS-CoV-2 coronavirus protease were exhibited highest affinity in terms of MolDock score (-167.203Kcal/mol), and hydroxychloroquine was found with lowest target affinity (-55.917 Kcal/mol).The amino acid residue cysteine 145 and histidine 41 is bound covalently and formed hydrogen bond interaction with SARS-CoV-2 inhibitor known as inhibitor N3 as such, hydroxychloroquine and azithromycin also formed hydrogen bond interaction. The binding patterns of the inhibitor N3 of SARS-CoV-2 coronavirus main protease could be used as a guideline for medicinal chemist to explore their SARS-CoV-2 inhibitory potential. Copyright © RJPT All right reserved.

Study of Marine Natural Products as Anti-SARS-CoV-2 Agents Using Molecular Modeling

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created a global pandemic. Viral entry into host cells is mediated by spike glycoprotein (SGP) interactions with angiotensin-converting enzyme 2 (ACE2) and heparan sulfate glycosaminoglycans on the cell surface. Carbohydrate small molecules were found to bind to the receptor binding domain (RBD) of SGP, which also interacts with ACE2, forming a ternary complex. Moreover, glycans isolated from sea cucumber and red alga species exhibited anti-SARS-CoV-2 activities, presumably by blocking viral entry mediated through SGP-heparan sulfate interactions. Here we report a collection of computational studies conducted as part of a collaborative effort to investigate the effects of marine natural products (NPs) on the wild-type and N501Y mutant SGP RBD. Starting from an X-ray crystal structure of the RBD-ACE2 complex, a model of SGP RBD was built. To investigate the static and dynamic behavior of RBD-NP interactions, blind and site-targeted molecular docking using diverse docking programs (Glide, AutoDock Vina or ClusPro) was carried out, followed by extensive molecular dynamics simulations with two force fields (CHARMM36 or Glycam06) and binding free energy calculations. Predicted conformations of the NPs varied considerably when modeled in water or in complex with RBD. Five NP binding sites on the RBD were studied. NP binding specificities towards SARS-CoV-2 variants were explained and important RBD residues were identified. Statistical analyses of the stability of various protein-NP complexes during molecular dynamics simulations helped to differentiate pseudo-vs. real-binding sites. Our results provide significant insights into the importance of extensive molecular dynamics calculations in order to move beyond the limitations of molecular docking.

Lapachol and (alpha/beta)-lapachone as inhibitors of SARS-CoV-2 Main Protease (Mpro) and hACE-2: ADME properties, docking and dynamic simulation approaches

Background: Tabebuia impetiginosa is an important medicinal plant rich in lapachol, alpha-lapachone, and beta-lapachone known to possess several biological activities. Objective(s): In this study, we investigated the drug potential of lapachol, alpha-lapachone, and beta-lapachone using molecular docking, molecular dynamic (MD), and drug-likeness properties. Material(s) and Method(s): The computational study was performed using SwissADME software for the determination of the pharmacokinetic properties of the tested compounds. AutoDock Vina and Genetic Optimization for Ligand Docking (GOLD) were used for the docking analysis, and MD simulations were run using Schrodinger's Desmond Simulation. Result(s): The three compounds lapachol, alpha-lapachone, and beta-lapachone binds to cysteine (Cys)-histidine (His) catalytic dyad (Cys145 and His41) along with the other residues with, respectively, the following docking score 48.69, 47.06, and 47.79. Against viral entry receptor, human angiotensin-converting enzyme 2 (hACE-2), alpha-lapachone exhibited the highest GOLD Fitness score complex (54.82) followed by lapachol (42.53) and beta-lapachone and hACE-2 (38.74) generating several active sites in the target proteins. A 100 ns MDs simulation study revealed the stable conformation of bioactive compounds within the cavity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) of hACE-2 protein and main protease (Mpro). From the dynamic study, it was observed that lapachol was tightly bound with catalytic dyad residue Cys145 of Mpro with more than 40% time of simulation, also post-simulation MM-GBSA binding free energy (DELTAG Bind) revealed the highest energy score (-51.18 +/- 5.14 kcal/mol) among the evaluated complex. Moreover, the absorption, distribution, metabolism, and excretion (ADME) properties demonstrated that the investigated compounds passed the pharmacokinetic and drug-likeness criteria without undesirable effects. Conclusion(s): The computational study highlighted that these compounds could be highly recommended and developed as part of an effective drug against the SARS-CoV-2 virus. Copyright © 2022 Pharmacognosy Magazine.

Molecular Insights into Striking Antibody Evasion of SARS-CoV-2 Omicron Variant

The SARS-CoV-2 Omicron variant has become the dominant variant in the world. Uncovering the structural basis of altered immune response and enhanced transmission of Omicron is particularly important. Here, taking twenty-five antibodies from four groups as examples, we comprehensively reveal the underlying mechanism of how mutations in Omicron induces the weak neutralization by using molecular simulations. Overall, the binding strength of 68% antibodies is weakened in Omicron, much larger than that in Delta (40%). Specifically, the percentage of the weakened antibodies vary largely in different groups. Moreover, the mutation-induced repulsion is mainly responsive for the weak neutralization in AB/CD groups but does not take effect in EF group. Significantly, we demonstrate that the disappearance of hydrophobic interaction and salt bridges due to residue deletions contributes to the decreased binding energy in NTD group. This work provides unprecedented atomistic details for the distinct neutralization of WT/Delta/Omicron, which informs prospective efforts to design antibodies/vaccines against Omicron.

Advances in peptidomimetic inhibitors of coronavirus main protease

Coronavirus (CoVs) is a widespread pathogen that can infect humans and animals to cause serious acute and chronic respiratory diseases. Among them, SARS-CoV broke out in 2003, MERS-CoV was discovered and spread widely in 2012, and SARS-CoV-2 emerged at the end of 2019. They all belong to β-coronavirus. Peptidomimetic inhibitors targeting coronavirus main proteases (Mpro, 3CLpro) have attracted much attention because of their broad spectrum and strong antiviral efficacy. In this review, peptidomimetic inhibitors of coronavirus main protease were classified and summarized according to the different "warheads" in design strategy. And also, the molecular structures, biological activity and design ideas of the inhibitors were analyzed and discussed, which is aimed to provide useful reference for further design and development of coronavirus inhibitors.

SARS-CoV-2 variants impact RBD conformational dynamics and ACE2 accessibility

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed over 5 million people and is causing a devastating social and economic impact all over the world. The rise of new variants represents a difficult challenge due to the loss of vaccine and natural immunity, and increased transmissibility. These variants contain mutations in the spike glycoprotein, which mediates fusion between the viral and host cell membranes, via its receptor binding domain (RBD) that binds to angiotensin-converting enzyme 2 (ACE2). To understand the effect of RBD mutations, a lot of attention has been given to the RBD-ACE2 interaction. However, this type of analysis is limited since it ignores the conformational dynamics of the RBD itself. Observing that some variants mutations occur in residues that are not in direct contact with ACE2, we hypothesized that they could affect RBD conformational dynamics. To test this, we performed long atomistic molecular dynamics simulations to investigate the structural dynamics of wt RBD, and that of three variants (alpha, beta and delta). Our results show that in solution, wt RBD presents two distinct conformations: an 'open' conformation where it is free to bind ACE2;and a 'closed' conformation, where the RBM ridge blocks the binding surface. The alpha and beta variants significantly impact the open/closed equilibrium, shifting it towards the open conformation by roughly 20%. This shift likely increases ACE2 binding affinity. In the delta variant RBD simulations, the closed conformation was never observed. Instead, the system alternated between the before mentioned open conformation and an alternative 'reversed' one, with a significantly changed orientation of the RBMridge flanking the RBD. These results support the hypothesis that variants impact RBD conformational dynamics in a direction that simultaneously promotes efficient binding to ACE2 and antibody escape.