Innovative cascade reaction for 2H-indazole derivative synthesis.

In the realm of synthetic organic chemistry, by using a one-pot sequential combination of MCR, it is possible to manufacture chemical commodities (fine chemicals, agrochemicals, and pharmaceutical substances) that enhance our quality of life while generating less waste materials and increasing economic advantages. With this motivation, using a "one-pot" method with multiple components, we present a relatively simple way to make stereoselective substitute 2H-indazole analogues for this study. Firstly, functionalised 3-bromo-4-((methylthio)methyl) derivatives were produced using DMSO as both a carbon source and a solvent, in conjunction with TMSOTf as the Lewis acid promoter. These derivatives were then utilised in the synthesis of 2-H-indazole derivatives with an up to 80% yield using t-Bu3PHBF4 as the ligand and Cs2CO3 as the base, in the presence of a Pd catalyst at 100°C in an airtight tube. The phenyl ring is endowed with an electron-releasing group situated at position C-6, which efficiently synthesises several 2-H-indazol derivatives with cost-efficient and noteworthy yields by using this method. A comparative analysis of a number of halogen derivatives was also undertaken, using a variety of solvents that were classified according to their halogen group. To confirm the structures of the synthesised target compounds, spectrometric analysis (1H NMR, 13C NMR, and LCMS) was performed.

Understanding mastitis: Microbiome, control strategies, and prevalence - A comprehensive review.

Mastitis significantly affects the udder tissue in dairy cattle, leading to inflammation, discomfort, and a decline in both milk yield and quality. The condition can be attributed to an array of microbial agents that access the mammary gland through multiple pathways. The ramifications of this ailment are not merely confined to animal welfare but extend to the financial viability of the livestock industry. This review offers a historical lens on mastitis, tracing its documentation back to 1851, and examines its global distribution with a focus on regional differences in prevalence and antimicrobial resistance (AMR) patterns. Specific microbial genes and communities implicated in both mastitis and AMR are explored, including Staphylococcus aureus, Streptococcus agalactiae,Streptococcus dysagalactiae, Streptococcus uberis Escherichia coli, Klebsiella pneumoniae, Mycoplasma bovis, Corynebacterium bovis, among others. These microorganisms have evolved diverse strategies to elude host immune responses and neutralize commonly administered antibiotics, complicating management efforts. The review aims a comprehensive overview of the current knowledge and research gaps on mastitis and AMR, and to highlight the need for a One Health approach to address this global health issue. Such an approach entails multi-disciplinary cooperation to foster judicious antibiotic use, enhance preventive measures against mastitis, and bolster surveillance and monitoring of AMR in pathogens responsible for mastitis.

Comprehensive computational investigation for ligand recognition and binding dynamics of SdiA: a degenerate LuxR -type receptor in Klebsiella pneumoniae.

SdiA is a LuxR-type receptor that controls the virulence of Klebsiella pneumoniae, a Gram-negative bacterium that causes various infections in humans. SdiA senses exogenous acyl-homoserine lactones (AHLs) and autoinducer-2 (AI-2), two types of quorum sensing signals produced by other bacterial species. However, the molecular details of how SdiA recognizes and binds to different ligands and how this affects its function and regulation in K. pneumoniae still need to be better understood. This study uses computational methods to explore the protein-ligand binding dynamics of SdiA with 11 AHLs and 2 AI-2 ligands. The 3D structure of SdiA was predicted through homology modeling, followed by molecular docking with AHLs and AI-2 ligands. Binding affinities were quantified using MM-GBSA, and complex stability was assessed via Molecular Dynamics (MD) simulations. Results demonstrated that SdiA in Klebsiella pneumoniae exhibits a degenerate binding nature, capable of interacting with multiple AHLs and AI-2. Specific ligands, namely C10-HSL, C8-HSL, 3-oxo-C8-HSL, and 3-oxo-C10-HSL, were found to have high binding affinities and formed critical hydrogen bonds with key amino acid residues of SdiA. This finding aligns with the observed preference of SdiA for AHLs having 8 to 10 carbon-length acyl chains and lacking hydroxyl groups. In contrast, THMF and HMF demonstrated poor binding properties. Furthermore, AI-2 exhibited a low affinity, corroborating the inference that SdiA is not the primary receptor for AI-2 in K. pneumoniae. These findings provide insights into the protein-ligand binding dynamics of SdiA and its role in quorum sensing and virulence of K. pneumoniae.

Pinpointing top inhibitors for GSK3ß from pool of indirubin derivatives using rigorous computational workflow and their validation using molecular dynamics (MD) simulations.

Glycogen synthase kinase-3ß (GSK3ß) is a pivotal protein kinase implicated in a spectrum of debilitating diseases, encompassing cancer, diabetes, and neurodegenerative disorders. While the therapeutic potential of GSK3ß inhibition is widely recognized, there remains an unmet need for a rigorous, systematic analysis probing the theoretical inhibition dynamics of a comprehensive library of indirubin derivatives against GSK3ß using advanced computational methodologies. Addressing this gap, this study embarked on an ambitious endeavor, leveraging indirubin-a renowned scaffold-as a template to curate a vast library of 1000 indirubin derivatives from PubChem. These were enriched with varied substitutions and modifications, identified via a structure similarity search with a Tanimoto similarity threshold of 85%. Harnessing a robust virtual screening workflow, we meticulously identified the top 10 contenders based on XP docking scores. Delving deeper, we gauged the binding free energy differentials (ΔGBind) of these hits, spotlighting the top three compounds that showcased unparalleled binding prowess. A comparative pharmacophore feature mapping with the reference inhibitor OH8, co-crystallized with GSK3ß (PDB ID: 6Y9R), was undertaken. The binding dynamics of these elite compounds were further corroborated with 100 ns molecular dynamics simulations, underlining their stable and potent interactions with GSK3ß. Remarkably, our findings unveil that these indirubin derivatives not only match but, in certain scenarios, surpass the binding affinity and specificity of OH8. By bridging this research chasm, our study amplifies the therapeutic promise of indirubin derivatives, positioning them as frontrunners in the quest for groundbreaking GSK3ß inhibitors, potentially revolutionizing treatments for a myriad of ailments.

The development of thymol-isatin hybrids as broad-spectrum antibacterial agents with potent anti-MRSA activity.

Bacterial resistance toward available therapeutic agents has become a nightmare for the healthcare system, causing significant mortality as well as prolonged hospitalization, thereby needing the urgent attention of research groups working on antimicrobial drug development worldwide. Molecular hybridization is a well-established tool for developing multifunctional compounds to tackle drug resistance. Inspired by the antibacterial profiles of isatin and thymol, along with the efficiency of a triazole linker in molecular hybridization, herein, we report the design, synthesis and antibacterial activity of a novel series of triazole tethered thymol-isatin hybrids. Most of the hybrids exhibited a broad-spectrum antibacterial efficacy against standard human pathogenic as well as clinically isolated multidrug-resistant bacterial strains listed in the WHO's 'priority pathogen' list and also in the ESKAPE group. Among them, hybrid compound AS8 was the most effective against methicillin-resistant Staphylococcus aureus (MIC = 1.9 µM and MBC = 3.9 µM), exhibiting biofilm inhibitory potential. AS8 exhibited dehydrosqualene synthase (CrtM) inhibitory potential in MRSA and decreased the production of virulence factor staphyloxanthin, which is one of the key mechanisms of its anti-MRSA efficacy, which was further supported by molecular docking and simulation studies. Moreover, AS8 was found to be non-toxic and showed a potent in vivo antibacterial efficacy (90% survival at 10 mg kg-1) as well as a modulated immune response in the larva-based (Galleria mellonella) model of systemic infections. Overall findings confirmed that AS8 can be a promising candidate or take the lead in the treatment and further drug development against drug-resistant infectious diseases, especially against MRSA infections.

Probing the effects of streptomycin on Brassica napus germination and assessing its molecular interactions using extensive molecular dynamics (MD) simulations.

Antibiotics are chemical compounds that are used to treat and prevent disease in humans and animals. They have been used in animal feed for over 60 years and are widely used in industrial farming. Antibiotics can have negative environmental impacts, including the potential to contribute to the development of antibiotic-resistant organisms. They can enter the environment through various pathways, including the manufacturing process, the direct application of antibiotic-laden manure to fields, and through grazing animals. Antibiotics that are given to animals can be excreted from where they can enter soil and groundwater which enable their entry in plants. Streptomycin is an antibiotic that is used against a range of gram-positive and gram-negative bacteria, but its use has led to the development of antibiotic resistance in some pathogens. It has also been shown to have negative impacts on a range of plant species, including tobacco, tomato, and wheat. Although, the major effect of streptomycin on plant physiology have been studied, the molecular mechanisms at play are barely understood in plant body. In current study, we examined the impact of streptomycin on germination of Brassica napus and then using docking, MM-GBBSA and MD simulations identified key proteins that interact with streptomycin by performing rigorous computational screening of 106 different proteins. Our finding suggest that streptomycin might be interacting with acyl-CoA oxidases, protochlorophyllide reductase B and leucoanthocyanidin dioxygenase based on simulation and docking analysis.

Characterizing and demonstrating the role of Klebsiella SSN1 exopolysaccharide in osmotic stress tolerance using neutron radiography.

Exopolysaccharides (EPS) are organic macromolecules naturally secreted by many microorganisms. EPS is increasingly used for agriculture and industrial purposes. This study focuses on isolate Klebsiella pneumonia SSN1, Klebsiella quasipeumonniae SGM81 isolated from rhizosphere to explore its water retention efficiency under drought conditions. Neutron Radiography was used to visualise water distribution in the sand under normal and drought conditions in the presence and absence of EPS producing bacteria. The EPS production was studied by applying Box Behnken design (BBD) under drought stress which was artificially induced by using polyethene glycol 6000 under osmotic stress condition 3.65% w/v of EPS dry weight was obtained. The relative water content (RWC) is used to calculate the amount of water present in the sand and was further studied by Neutron Radiography imaging with appropriate controls. FTIR and HPLC were also carried out for the characterisation of the extracted EPS. The sand experiments revealed that after 24 h of evaporation, the highest RWC was maintained by SSN1 at 29.7% compared to SGM81 (19.06%). SSN1 was found to release L-arabinose as the main sugar of its EPS under drought stress conditions by HPLC method. The FTIR data indicated the presence of ß-glucans and polysaccharide α-pyranose between wavenumber 700 cm-1-1500 cm-1 and 1017 cm-1-1200 cm-1 respectively. The HPLC characterization of extracted EPS from osmotic stressed cells (run 3) displayed a peak designated to L-arabinose at 10.3 retention time (RT) for 132.4 mM concentration. While from run 5 with the controlled condition indicated the presence of L-rhamnose at 7.3 RT for 87 mM concentration. Neutron radiography enables the visualisation of water distribution in the sand as well as water transport in root-soil systems in situ. SSN1 has elicited EPS production in drought conditions with a low level of nitrogen and carbon.

Curcumin interferes with chitin synthesis in Aedes aegypti: a computational and experimental investigation.

Throughout history, vector-borne diseases have consistently posed significant challenges to human health. Among the strategies for vector control, chemical insecticides have seen widespread use since their inception. Nevertheless, their effectiveness is continually undermined by the steady growth of insecticide resistance within these vector populations. As such, the demand for more robust, efficient, and cost-effective natural insecticides has become increasingly pressing. One promising avenue of research focuses on chitin, a crucial structural component of mosquitoes' exoskeletons and other insects. Chitin not only provides protection and rigidity but also lends flexibility to the insect body. It undergoes substantial transformations during insect molting, a process known as ecdysis. Crucially, the production of chitin is facilitated by an enzyme known as chitin synthase, making it an attractive target for potential novel insecticides. Our recent study delved into the impacts of curcumin, a natural derivative of turmeric, on chitin synthesis and larval development in Aedes aegypti, a mosquito species known to transmit dengue and yellow fever. Our findings demonstrate that even sub-lethal amounts of curcumin can significantly reduce overall chitin content and disrupt the cuticle development in the 4th instar larvae of Aedes aegypti. Further to this, we utilized computational analyses to investigate how curcumin interacts with chitin synthase. Techniques such as molecular docking, pharmacophore feature mapping, and molecular dynamics (MD) simulations helped to illustrate that curcumin binds to the same site as polyoxin D, a recognized inhibitor of chitin synthase. These findings point to curcumin's potential as a natural, bioactive larvicide that targets chitin synthase in mosquitoes and potentially other insects.

A clash of quorum sensing vs quorum sensing inhibitors: an overview and risk of resistance.

Indiscriminate use of antibiotics to treat microbial pathogens has caused emergence of multiple drug resistant strains. Most infectious diseases are caused by microbes that are capable of intercommunication using signaling molecules, which is known as quorum sensing (QS). Such pathogens express their pathogenicity through various QS-regulated virulence factors. Interference of QS could lead to decisive results in controlling such pathogenicity. Hence, QS inhibition has become an attractive new approach for the development of novel drugs. Many quorum sensing inhibitors (QSIs) of diverse origins have been reported. It is imperative that more such anti-QS compounds be found and studied, as they have significant effect on microbial pathogenicity. This review attempts to give a brief account of QS mechanism, its inhibition and describes some compounds with anti-QS potential. Also discussed is the possibility of emergence of quorum sensing resistance.

Excavating phytochemicals from plants possessing antiviral activities for identifying SARS-CoV hemagglutinin-esterase inhibitors by diligent computational workflow.

Coronaviruses (CoVs) belong to a group of RNA viruses that cause diseases in vertebrates including. Newer and deadlier than SARS CoV-2 are sought to appear in future for which the scientific community must be prepared with the strategies for their control. Spike protein (S-protein) of all the CoVs require angiotensin-converting enzyme2 (ACE2), while CoVs also require hemagglutinin-acetylesterase (HE) glycoprotein receptor to simultaneously interact with O-acetylated sialic acids on host cells, both these interactions enable viral particle to enter host cell leading to its infection. Target inhibition of viral S-protein and HE glycoprotein receptor can lead to a development of therapy against the SARS CoV-2. The proposition is to recognize molecules from the bundle of phytochemicals of medicinal plants known to possess antiviral potentials as a lead that could interact and mask the active site of, HE glycoprotein which would ideally bind to O-acetylated sialic acids on human host cells. Such molecules can be addressed as 'HE glycoprotein blockers'. A library of 110 phytochemicals from Withania somnifera, Asparagus racemosus, Zinziber officinalis, Allium sativum, Curcuma longa and Adhatoda vasica was constructed and was used under present study. In silico analysis was employed with plant-derived phytochemicals. The molecular docking, molecular dynamics simulations over the scale of 1000 ns (1 µs) and ADMET prediction revealed that the Withania somnifera (ashwagandha) and Asparagus racemosus (shatavari) plants possessed various steroidal saponins and alkaloids which could potentially inhibit the COVID-19 virus and even other CoVs targeted HE glycoprotein receptor.Communicated by Ramaswamy H. Sarma.

Rapid method for detection, quantification and measuring microbial degradation of pesticide-thiram using high performance thin layer chromatography (HPTLC).

Thiram (tetramethylthiuramdisulfide) or thiram sulphide is a dithiocarbamate group of non-systemic group of fungicide which are applied for seed treatment, control of the crop pests, to repel animals, etc. Moreover, thiram has also been responsible to cause moderate skin sensitivity and eye irritation. Higher exposure to thiram might also lead to developmental damages to newborn and neurotoxic effects to non-target organisms. Advancing to prevent such toxic effects and prevention of soil fertility from thiram and thiram-like chemicals is indispensable. The analytical High-Performance Thin-Layer Chromatography (HPTLC) is a simple, quick and a reliable method was proposed and validated for the detection and quantification of various small molecules for many years. This manuscript represents the solution to use microbes to degrade the thiram present in the soil and for that, HPTLC based method to study thiram degradation by Pseudomonas has been designed. Herein, a HPTLC protocol formalised to reveal the detection and quantification of thiram within the range of 100 to 700 ng/spot on TLC plate. The same concentration was then used for calculating percent microbial degradation of thiram from the culture broth. To perform the microbial degradation of thiram, Pseudomonas otitidis strain TD-8 and Pseudomonas stutzeri strain TD-18 were taken as thiram degrader microbial strain. The efficacy of TD-8 to degrade thiram was identified to be 81 and 99% when grown in presence of thiram for 4 days and 8 days, respectively, while TD-18 strain's efficacy to degrade thiram was found to be 57% and 99% when grown in presence of thiram for 4 days and 8 days, respectively.

A Comprehensive in vitro and in silico Assessment on Inhibition of CYP51B and Ergosterol Biosynthesis by Eugenol in Rhizopus oryzae.

Mucormycosis, also known as Zygomycosis, is a disease caused by invasive fungi, predominantly Rhizopus species belonging to the Order of Mucorales. Seeing from the chemistry perspective, heterocyclic compounds with an "azole" moiety are widely employed as antifungal agent for minimising the effect of mucormycosis as a prescribed treatment. These azoles serve as non-competitive inhibitors of fungal CYP51B by predominantly binding to its heme moiety, rendering its inhibition. However, long-term usage and abuse of azoles as antifungal medicines has resulted in drug resistance among certain fungal pathogens. Hence, there is an unmet need to find alternative therapeutic compounds. In present study, we used various in vitro tests to investigate the antifungal activity of eugenol against R. oryzae/R. arrhizus, including ergosterol quantification to test inhibition of ergosterol production mediated antifungal action. The minimum inhibitory concentration (MIC) value obtained for eugenol was 512 µg/ml with reduced ergosterol concentration of 77.11 ± 3.25% at MIC/2 concentration. Further, the molecular interactions of eugenol with fungal CYP51B were meticulously studied making use of proteomics in silico study including molecular docking and molecular dynamics simulations that showed eugenol to be strongly interacting with heme in an identical fashion to that shown by azole drugs (in this case, clotrimazole was evaluated). This is the first of a kind study showing the simulation study of eugenol with CYP51B of fungi. This inhibition results in ergosterol synthesis and is also studied and compared with keeping clotrimazole as a reference.

Potential dual inhibition of SE and CYP51 by eugenol conferring inhibition of Candida albicans: Computationally curated study with experimental validation.

Ergosterol is the key sterol component in the cell membrane of fungi including moulds and yeasts. Any decrease in the levels of ergosterol in the cell membrane of fungi render them venerable to cell membrane damage and even its death. Majority of antifungal drug targets the key enzymes involved in ergosterol biosynthesis pathway. The biochemical pathway for the synthesis of Ergosterol is a complex one, though the reactions carried by Squalene Epoxidase (SE) and 14α-demethylase (CYP51- a member of Cytochrome P450 family) serves to the key rate limiting reactions that can impact the overall production of Ergosterol. Allylamines class of antifungal drug target SE while Azoles target the CYP51. Currently advancement in the drug development is focused to introduce newer drugs that can simultaneously inhibit both this rate limiting enzymes. However, natural compounds established to possess antifungal activity but the major loophole about their understanding lies in the fact that their mode of action are severely unstudied. One such well-established antifungal natural phytochemical is Eugenol, and in current manuscript we investigated its efficacy to interact with both, SE and CYP51 of Candida albicans using molecular Docking, Free energy change calculations and Molecular Dynamics (MD) simulation, showing promising outcomes. For experimental studies, terbinafine, clotrimazole and eugenol showed 4 µg/ml, 2 µg/ml, and 512 µg/ml MIC90 values, respectively against C. albicans and also showed reduction in Ergosterol production at sub-MIC levels. The obtained result indicates the involvement of eugenol in the inhibition of enzymes require in the ergosterol biosynthesis pathway.

Molecular insights on ar-turmerone as a structural, functional and pharmacophoric analogue of synthetic mosquito repellent DEET by comprehensive computational assessment.

Mosquitoes are vectors for a variety of infectious illnesses, and chemical synthetic insecticides have made it possible to control them effectively. Mosquito repellents are a typical means of keeping mosquitos at bay. Because of its main effectiveness of skin permeability, N,N-Diethyl-meta-toluamide (DEET) is one of the most extensively used mosquito repellents but a dangerous synthetic chemical. DEET was identified about a decade ago to inhibit mosquito's Odorant Binding Protein 1 (OBP1), impairing the mosquito's ability to recognise the host body odour. OBP1 has been identified as a possible target for the development of new mosquito repellents since its discovery. Essential oils from different plants, on the other hand, have been used to repel mosquitos since antiquity. One essential oil from the Curcuma longa (Zingiberales: Zingiberaceae) rhizome display mosquito repellent properties, according to the literature. Furthermore, one of the phytochemicals found in abundance in C. longa essential oil, ar-turmerone, exhibits mosquito repellency as comparable to synthetic DEET. Till date studies on in-silico interaction of natural ar-turmerone with OBP1, which we depict in our current work are scarce. Further, there exist no published reports demonstrating the literary evidence on detailed insights of interaction of DEET with OBP1 along with Molecular Dynamics (MD) simulation studies. We further performed detailed molecular investigations using pharmacophore analysis of ar-turmerone and compared it with DEET, where our findings in the current manuscript unveils for the first time that ar-turmerone is a functional, structural and pharmacophoric analogue of DEET.

Identification of potential therapeutic targets associated with diagnosis and prognosis of colorectal cancer patients based on integrated bioinformatics analysis.

Colorectal cancer (CRC) is the most common malignancy of digestive system with significant mortality rate. CRC patients with comparable clinical symptoms or at similar stages of the disease have different outcomes. This underlying clinical result is almost inevitably due to genetic heterogeneity. Therefore, the current study aimed to highlight gene signatures during CRC and unveil their potential mechanisms through bioinformatic analysis. The gene expression profiles (GSE28000, GSE33113, GSE44861, and GSE37182) were downloaded from the Gene Expression Omnibus database, and the differential expressed genes (DEGs) were identified in normal tissues and tumor tissue samples of CRC patients. In total, 8931 DEGs were identified in CRC, including 411 up-regulated genes and 166 down-regulated genes. Further, a protein-protein interaction network was constructed and the highly related genes were clustered using the Molecular Complex Detection algorithm (MCODE) to retrieve the core interaction in different genes' crosstalk. The screened hub genes were subjected to functional enrichment analysis. GO analysis results showed that up-regulated DEGs were significantly enriched in biological processes (BP), including cell division, cell cycle, and cell proliferation; the down-regulated DEGs were significantly enriched in BP, including cellular homeostasis, detoxification, defense response, intracellular signaling cascade. Additionally, KEGG pathway analysis displayed the up-regulated DEGs were enriched in the cell cycle, TNF signaling, chemokine signaling pathway, while the down-regulated DEGs were enriched in NF-kB signaling, mineral reabsorption. Furthermore, the overall survival and expression levels of hub genes were detected by the UALCAN database and were further validated using Human Protein Atlas database. Taken together the identified DEGs (MT2A, CCNB1, DLGAP5, CCNA2, CXCL2, and RACGAP1) enhance our understanding of the molecular pathways that underpin CRC pathogenesis and could be exploited as molecular targets and diagnostic biomarkers for CRC therapy.

Extending the lore of curcumin as dipteran Butyrylcholine esterase (BChE) inhibitor: A holistic molecular interplay assessment.

Since its origin, the emergence of vector-borne infections has taken a toll on incalculable human lives. The use of chemical insecticides is one of the early known methods of vector control and although their use is still a prevalent way to combat insect population sadly the perils of insects related transmission still persists. Most commonly, the existing insecticides face the wrath of getting resisted repeatedly, paying way to develop resilient, efficient, and cost-effective natural insecticides. In this study, computational screening was performed using homology modelling, E-pharmacophore feature mapping, molecular docking, Density Function Theory (DFT) assessment, Molecular mechanics generalized Born surface area (MM-GBSA) based binding free energy calculations and Molecular Dynamics (MD) simulation to identify a potential lead phytochemical out of a manually curated library from published literature. The protein target used under this study is insect Butyrylcholine esterase (BChE). Additionally, in vitro insect (Aedes aegypti) BChE inhibition assay was also performed with the top phytochemical identified from in silico assessments. Our research highlights that curcumin leads to inhibition of enzyme BChE of Ae. aegypti. The identified mode of action of curcumin as an insect BChE inhibitor indicates the possibility of its use as an environment friendly and natural futuristic insecticide.

Perceiving SARS-CoV-2 Mpro and PLpro dual inhibitors from pool of recognized antiviral compounds of endophytic microbes: an in silico simulation study.

Coronavirus disease 2019 (COVID-19) persists and shook the global population where the endgame to this pandemic is brought on by developing vaccines in record-breaking time. Nevertheless, these vaccines are far from perfect where their efficiency ranges from 65 to 90%; therefore, vaccines are not the one only solution to overcome this situation, and apart from administration of vaccines, the scientific community is at quest for finding alternative solutions to incumber SARS-CoV-2 infection. In this study, our research group is keen on identifying a bioactive molecule that is independent in its mode of action from existing vaccines which can potentially target the SARS-CoV-2 virus replicative efficacy. Papain-like protease (PLpro) and main protease (Mpro) are the most lucrative targets of COVIDs against which the drugs can be developed, as these proteases play a vital role in the replication and development of viral particles. Researchers have modelled a compound such as GRL0617 and X77 as an inhibitor of Mpro and PLpro, respectively, but use of these compounds has several limitations on hosts like toxicity and solubility. Under the current study by deploying rigorous computational assessments, pool of microbial secondary metabolites was screened and handpicked to search a structural or functional analogue of GRL0617 and X77, with an idea to identify a compound that can serve as dual inhibitor for both PLpro and Mpro. From the manually curated database of known antiviral compounds from fungal origin, we found cytonic acids A and B to potentially serve as dual inhibitor of PLpro and Mpro.

Proposing a fungal metabolite-flaviolin as a potential inhibitor of 3CLpro of novel coronavirus SARS-CoV-2 identified using docking and molecular dynamics.

The novel SARS-CoV-2 is the etiological agent causing the Coronavirus disease 2019 (COVID-19), which continues to become an inevitable pandemic outbreak. Over a short span of time, the structures of therapeutic target proteins for SARS-CoV-2 were identified based on the homology modelled structure of similar virus, SARS-CoV that transmitted rapidly in 2003. Since the outset of the disease, the research community has been looking for a potential drug lead. Out of all the known resolved structures related to SARS-CoV-2; 3-chymotrypsin (3 C) like protease (3CLpro) is considered as an attractive anti-viral drug compound on the grounds of its role in viral replication and probable non-interactive competency to bind to any viral host protein. To the best of our knowledge, till date only one compound has been identified and tested in-vitro as a potent inhibitor of 3CLpro protein, addressed as N3 (PubChem Compound CID: 6323191) and is known to bind irreversibly to 3CLpro suppressing its activity. Using computational approach, we intend to identify a probable natural fungal metabolite to interact and inhibit 3CLpro. Here after performing docking and molecular dynamics of various small molecules derived as a secondary metabolite from fungi, we propose Flaviolin as potent inhibitor of 3CLpro of novel Coronavirus SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Curse of La Corona: unravelling the scientific and psychological conundrums of the 21st century pandemic.

Microbes possess a tremendous potential to interact with their surroundings and have continued to shape the future of all life forms existing on earth. Of all the groups of microbes, viruses are the most nefarious creatures which cannot be solely classified as living or non-living but still pose the greatest threats to the biosphere. Viruses are minuscule, diverse and are probably the only entities that exhibit non-mutualistic association with other lifeforms while retaining their ability to infect and hijack any of the existing living being on the planet. The latest global devastation, caused by novel SARS-CoV-2, is unparalleled in the last century. This review encompasses the mysterious origin of this virus by tracking its lineage, which may help to decode the conundrum of SARS-CoV-2 and shed more light on its epidemiology. The implications and the challenge posed by this virus to the scientific community to the medical community and the economy at large are reflected. Also discussed is the paradigm shift brought upon by the COVID-19 pandemic on the human psyche and their behaviour.

Repurposing of anticancer phytochemicals for identifying potential fusion inhibitor for SARS-CoV-2 using molecular docking and molecular dynamics (MD) simulations.

The viral particle, SARS-CoV-2 is responsible for causing the epidemic of Coronavirus disease 2019 (COVID-19). To combat this situation, numerous strategies are being thought for either creating its antidote, vaccine, or agents that can prevent its infection. For enabling research on these strategies, several target proteins are identified where, Spike (S) protein is of great potential. S-protein interacts with human angiotensin-converting-enzyme-2 (ACE2) for entering the cell. S-protein is a large protein and a portion of it designated as a receptor-binding domain (RBD) is the key region that interacts with ACE2, following to which the viral membrane fuses with the alveolar membrane to enter the human cell. The hypothesis is to identify molecules from the pool of anticancer phytochemicals as a lead possessing the ability to interact and mask the amino acids of RBD, making them unavailable to form associations with ACE2. Such a molecule is termed as 'fusion inhibitor'. We hypothesized to identify fusion inhibitors from the NPACT library of anticancer phytochemicals. For this, all the molecules from the NPACT were screened using molecular docking, the five top hits (Theaflavin, Ginkgetin, Ursolic acid, Silymarin and Spirosolane) were analyzed for essential Pharmacophore features and their ADMET profiles were studied following to which the best two hits were further analyzed for their interaction with RBD using Molecular Dynamics (MD) simulation. Binding free energy calculations were performed using MM/GBSA, proving these phytochemicals containing anticancer properties to serve as fusion inhibitors.Communicated by Ramaswamy H. Sarma.