Predictive modeling and therapeutic repurposing of natural compounds against the receptor-binding domain of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a member of the Coronaviridae family, causing major destructions to human life directly and indirectly to the economic crisis around the world. Although there is significant reporting on the whole genome sequences and updated data for the different receptors are widely analyzed and screened to find a proper medication. Only a few bioassay experiments were completed against SARS-CoV-2 spike protein. We collected the compounds dataset from the PubChem Bioassay database having 1786 compounds and split it into the ratio of 80-20% for model training and testing purposes, respectively. Initially, we have created 11 models and validated them using a fivefold validation strategy. The hybrid consensus model shows a predictive accuracy of 95.5% for training and 94% for the test dataset. The model was applied to screen a virtual chemical library of Natural products of 2598 compounds. Our consensus model has successfully identified 75 compounds with an accuracy range of 70-100% as active compounds against SARS-CoV-2 RBD protein. The output of ML data (75 compounds) was taken for the molecular docking and dynamics simulation studies. In the complete analysis, the Epirubicin and Daunorubicin have shown the docking score of -9.937 and -9.812, respectively, and performed well in the molecular dynamics simulation studies. Also, Pirarubicin, an analogue of anthracycline, has widely been used due to its lower cardiotoxicity. It shows the docking score of -9.658, which also performed well during the complete analysis. Hence, after the following comprehensive pipeline-based study, these drugs can be further tested in vivo for further human utilization.Communicated by Ramaswamy H. Sarma.

Reporting dinaciclib and theodrenaline as a multitargeted inhibitor against SARS-CoV-2: an in-silico study.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is one of the rapid spreading coronaviruses that belongs to the Coronaviridae family. The rapidly evolving nature of SARS-CoV-2 results in a variety of variants with a capability of evasion to existing therapeutics and vaccines. So, there is an imperative need to discover potent drugs that can able to disrupt the function of multiple drug targets to tackle the SARS-CoV-2 menace. Here in this study, we took the different targets of SARS-CoV-2 prepared in the Schrodinger maestro. The library of the DrugBank database is screened against the selected crucial targets. Our molecular docking, Molecular Mechanics/Generalized Born Surface Area (MMGBSA), and molecular dynamics simulation studies led to identifying dinaciclib and theodrenaline as potential drugs against multiple drug targets: main protease, NSP15-endoribonuclease and papain-like-protease, of SARS-CoV-2. Dinaciclib with papain-like protease and NSP15-endoribonuclease show the docking score of -7.015 and -8.737, respectively, while the theodrenaline with NSP15-endoribonuclease and main protease produced the docking score of -8.507 and -7.289, respectively. Furthermore, the binding free energy calculations with MM/GBSA and molecular dynamics simulation studies of the complexes confirm the reliability of the drugs. The selected drugs are capable of binding to multiple targets simultaneously, thus withstanding their activity of target disruption in different variants of SARS-CoV-2. Although, the repurposed drugs are showing potent activity, but may need further in-vitro and in-vivo validations.Communicated by Ramaswamy H. Sarma.

Evaluation of Clove Phytochemicals as Potential Antiviral Drug Candidates Targeting SARS-CoV-2 Main Protease: Computational Docking, Molecular Dynamics Simulation, and Pharmacokinetic Profiling.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus can cause a sudden respiratory disease spreading with a high mortality rate arising with unknown mechanisms. Still, there is no proper treatment available to overcome the disease, which urges the research community and pharmaceutical industries to screen a novel therapeutic intervention to combat the current pandemic. This current study exploits the natural phytochemicals obtained from clove, a traditional natural therapeutic that comprises important bioactive compounds used for targeting the main protease of SARS-CoV-2. As a result, inhibition of viral replication effectively procures by targeting the main protease, which is responsible for the viral replication inside the host. Pharmacokinetic studies were evaluated for the property of drug likeliness. A total of 53 bioactives were subjected to the study, and four among them, namely, eugenie, syzyginin B, eugenol, and casuarictin, showed potential binding properties against the target SARS-CoV-2 main protease. The resultant best bioactive was compared with the commercially available standard drugs. Furthermore, validation of respective compounds with a comprehensive molecular dynamics simulation was performed using Schrödinger software. To further validate the bioactive phytochemicals and delimit the screening process of potential drugs against coronavirus disease 2019, in vitro and in vivo clinical studies are needed to prove their efficacy.

Cytogenetic Consequences of Food Industry Workers Occupationally Exposed to Cooking Oil Fumes (COFs).

BACKGROUND: Cooking oil fumes (COFs) with smoking habits is a substantial risk that aggravates genetic modifications. The current study was to estimate the biological markers of genetic toxicity counting Micronucleus changes (MN), Chromosome Aberrations (CA) and DNA modifications among COFs exposures and control subjects inherent from South India. MATERIALS AND METHODS: Present analysis comprised 212 COFs with tobacco users and equivalent number of control subjects. RESULTS: High frequency of CA (Chromatid type: and chromosome type) were identified in group II experimental subjects also high amount of MN and DNA damage frequency were significantly (p < 0.05) in both subjects (experimental smokers and non-smokers). Present analysis was observed absence of consciousness among the COFs exposures about the destructive level of health effects of tobacco habits in working environment. CONCLUSION: COFs exposed workers with tobacco induce the significant alteration in chromosomal level. Furthermore, a high level of rate of genetic diseases (spontaneous abortion) were identified in the experimental subjects. This finding will be helpful for preventive measures of COFs exposed workers and supportive for further molecular analysis.

Revisiting CRISPR/Cas-mediated crop improvement: Special focus on nutrition.

Genome editing (GE) technology has emerged as a multifaceted strategy that instantaneously popularised the mechanism to modify the genetic constitution of an organism. The clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated (Cas) protein-based genome editing (CRISPR/Cas) approach has huge potential for efficacious editing of genomes of numerous organisms. This framework has demonstrated to be more economical in contrast to mega-nucleases, zinc-finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs) for its flexibility, versatility, and potency. The advent of sequence-specific nucleases (SSNs) allowed the precise induction of double-strand breaks (DSBs) into the genome, ensuring desired alterations through non-homologous end-joining (NHEJ) or homology-directed repair (HDR) pathways. Researchers have utilized CRISPR/Cas-mediated genome alterations across crop varieties to generate desirable characteristics for yield enhancement, enriched nutritional quality, and stressresistance. Here, we highlighted the recent progress in the area of nutritional improvement of crops via the CRISPR/Cas-based tools for fundamental plant research and crop genetic advancements. Application of this genome editing aids in unraveling the basic biology facts in plants supplemented by the incorporation of genome-wide association studies, artificial intelligence, and various bioinformatic frameworks, thereby providing futuristic model studies and their affirmations. Strategies for reducing the 'off-target' effects and the societal approval of genome-modified crops developed via this modern biotechnological approach have been reviewed.

Probing the effect of a plus 1bp frameshift mutation in protein-DNA interface of domestication gene, NAMB1, in wheat.

Transcription factor NAM-B1 has a major role in the process of senescence, which results in higher Fe and Zn concentrations in grains of wild wheat (T. durum; Td). The absence of the wild type NAMB1 in T. aestivum (Ta), one of the cardinal crops essential for more than 1/3rd of the global population, affects Fe and Zn remobilisation to the maturing grain from the flag leaf resulting in lesser micronutrient bioavailability. The cardinal difference in the NAMB1 gene between the two species is the absence of +1 bp allele in Ta. Insilico studies using NAMB1 from Td and Ta was performed to explore the variation in the interaction with the conserved cis-element DNA motif (CATGTG) as both the proteins share the same domain, but there are no in silico studies reported of these proteins. The secondary structure, 3D-modelling of the proteins, DNA-protein docking and dynamics have computed by Schrodinger Prime Suite. Predicted secondary structures were energy minimised using Macromodel and docking was performed based on binding energy and hydrogen bonds. Molecular dynamics simulation of NAMB1-Ta and NAMB1-Td individually and with the cis-element motif, performed for 100 ns, revealed significant variations in the protein-DNA interaction in Ta. This work provides the modelled 3D-interaction profile caused by a single bp frameshift mutation in understanding the difference in function between NAMB1 orthologs due to lack of NAC domain. The overall computational analysis reveals that NAMB1-Ta and NAMB1-Td proteins display a good amount of dissimilarity in their structure, dynamics and DNA-binding characteristics.Communicated by Ramaswamy H. Sarma.

Data Mining by Pluralistic Approach on CRISPR Gene Editing in Plants.

Genome engineering by site-specific nucleases enables reverse genetics and targeted editing of genomes in an efficacious manner. Contemporary revolutionized progress in targeted-genome engineering technologies based on Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-related RNA-guided endonucleases facilitate coherent interrogation of crop genome function. Evolved as an innate component of the adaptive immune response in bacterial and archaeal systems, CRISPR/Cas system is now identified as a versatile molecular tool that ensures specific and targeted genome modification in plants. Applications of this genome redaction tool-kit include somatic genome editing, rectification of genetic disorders or gene therapy, treatment of infectious diseases, generation of animal models, and crop improvement. We review the utilization of these synthetic nucleases as precision, targeted-genome editing platforms with the inherent potential to accentuate basic science "strengths and shortcomings" of gene function, complement plant breeding techniques for crop improvement, and charter a knowledge base for effective use of editing technology for ever-increasing agricultural demands. Furthermore, the emerging importance of Cpf1, Cas9 nickase, C2c2, as well as other innovative candidates that may prove more effective in driving novel applications in crops are also discussed. The mined data has been prepared as a library and opened for public use at www.lipre.org.