Stable Binding Energies Research Articles

The Phylogenomic Characterization of Planotetraspora Species and Their Cellulases for Biotechnological Applications.

This study aims to evaluate the in silico genomic characteristics of five species of the genus Planotetraspora: P. kaengkrachanensis, P. mira, P. phitsanulokensis, P. silvatica, and P. thailandica, with a view to their application in therapeutic research. The 16S rRNA comparison indicated that these species were phylogenetically distinct. Pairwise comparisons of digital DNA-DNA hybridization (dDDH) and OrthoANI values between these studied type strains indicated that dDDH values were below 62.5%, while OrthoANI values were lower than 95.3%, suggesting that the five species represent distinct genomospecies. These results were consistent with the phylogenomic study based on core genes and the pangenome analysis of these five species within the genus Planotetraspora. However, the genome annotation showed some differences between these species, such as variations in the number of subsystem category distributions across whole genomes (ranging between 1979 and 2024). Additionally, the number of CAZYme (Carbohydrate-Active enZYme) genes ranged between 298 and 325, highlighting the potential of these bacteria for therapeutic research applications. The in silico physico-chemical characteristics of cellulases from Planotetraspora species were analyzed. Their 3D structure was modeled, refined, and validated. A molecular docking analysis of this cellulase protein structural model was conducted with cellobiose, cellotetraose, laminaribiose, carboxymethyl cellulose, glucose, and xylose ligand. Our study revealed significant interaction between the Planotetraspora cellulase and cellotetraose substrate, evidenced by stable binding energies. This suggests that this bacterial enzyme holds great potential for utilizing cellotetraose as a substrate in various applications. This study enriches our understanding of the potential applications of Planotetraspora species in therapeutic research.

Precise target capture and the dynamic separation of Sn(IV) in highly acidic media by combining N and P donor covalent organic framework silica-based composite adsorbents

A silica-based adsorbent (P507@COF-TpAzo/SiO2) with nitrogen and phosphorus donors was prepared for industrial separation and recovery of Sn(IV) by in-situ growth of covalent organic framework (COF) on a silica substrate combined with vacuum impregnation. The materials were tested and analyzed by the scanning electron microscope (SEM), X-ray diffraction (XRD) and other characterization techniques, which demonstrated that the adsorbent has an enormous specific surface area, excellent heat resistance, and a regular morphological structure. The static experimental results showed that the adsorbent displayed remarkable selectivity for Sn(IV) in high HCl and HNO3 concentration environments, with excellent kinetics (∼60 min) and outstanding adsorption capacities (60.02 mg/g in 3 M HCl, 92.59 mg/g in 3 M HNO3) in different media at 3 M acidity. Cycle performance testing demonstrated that the adsorbent exhibited excellent stability (cycle times ≥8). Analysis using Fourier transform infrared spectroscopy (FT-IR) and X-ray photoelectron spectroscopy (XPS) showed that the synergistic adsorption results of N and P were reflected, mainly by the synergistic complexation of P=O and N=N-C. The potential sites for the adsorption of the adsorbent towards Sn(IV) were predicted by density functional theory (DFT) calculations, and the adsorbent demonstrated a more stable binding energy with Sn(IV). Finally, dynamic separation and efficient enrichment (>210) of Sn(IV) in highly acidic wastewater were realized by designing a penetrating column separation process. P507@COF-TpAzo/SiO2 satisfied the requirements of the dynamic adsorption experiments, bridging the research gap of dynamic separation, and provides a new strategy for the industrial removal and recovery of Sn(IV), as well as a way for environmental protection and industrial green production.

Understanding the Competition Mechanism between Na2O and CaO for the Formation of the Initial Layer of Zhundong Coal Ash

The contents of alkali and alkaline earth metals are higher in Zhundong coal, and there are serious problems of slagging and fouling during the combustion process. Therefore, it is of great significance to reveal the mechanism of slagging and fouling in the boiler of Zhundong coal. In this paper, first-principle calculations based on density functional theory are used to study the competition mechanism of alkaline metal oxides during the combustion process in Zhundong coal by establishing the Na2O(110)/CaO(100)-SiO2(100) double-layer interface model. The results show that the bond lengths of the surface of Na2O(110) and CaO(100) with SiO2(100) after adsorption were generally lengthened and the value of bond population became smaller, which formed a stable binding energy during the reaction. The electron loss of Na is 0.05 e, the electron loss of Ca is 0.03 e, and the electron loss of Na2O is greater than that of CaO. The charge transfer on the surface of Na2O with SiO2 is obviously higher than that of CaO and the orbital hybridization on the surface of CaO with SiO2 is weaker than that on the surfaces of Na2O with SiO2. Na2O is easier to react with SiO2 than CaO. The adsorption energies on the surface of Na2O and CaO with SiO2 are −5.56 eV and −0.72 eV, respectively. The adsorption energy of Na2O is higher than that of CaO, indicating that Na2O is more prone to adsorption reactions and formation of Na-containing minerals and other minerals, resulting in more serious slagging. In addition, the XRD analyses at different temperatures showed that Na-containing compounds appeared before Ca-containing ones, and the reaction activity of Na2O is stronger than that of CaO in the reaction process. The experimental results have good agreement with the calculation results. This provides strong evidence to reveal the slagging and fouling of Zhundong coal.

Efficient Synthesis of Mannopyranoside-based Fatty Acyl Esters: Effects of Acyl Groups on Antimicrobial Potential.

The approval of Sucrose Fatty Acid Esters (SFAEs) as food additives/ preservatives with antimicrobial potential has triggered enormous interest in discovering new biological applications. Accordingly, many researchers reported that SFAEs consist of various sugar moieties, and hydrophobic side chains are highly active against certain fungal species. This study aimed to conduct aregioselective synthesis of SAFE and check the effect of chain length and site of acylation (i.e., C-6 vs. C-2, C-3, C-4, and long-chain vs. short-chain) on antimicrobial potency. A direct acylation method maintaining several conditions was used for esterification. In vitro tests, molecular docking, and in silico studies were conducted using standard procedures. In vitro tests revealed that the fatty acid chain length in mannopyranoside esters significantly affects the antifungal activity, where C12 chains are more potent against Aspergillus species. In terms of acylation site, mannopyranoside esters with a C8 chain substituted at the C-6 position are more active in antifungal inhibition. Molecular docking also revealed that these mannopyranoside esters had comparatively better stable binding energy and hence better inhibition, with the fungal enzymes lanosterol 14-alpha-demethylase (3LD6), urate oxidase (1R51), and glucoamylase (1KUL) than the standard antifungal drug fluconazole. Additionally, the thermodynamic, orbital, drug-likeness, and safety profiles of these mannopyranoside esters were calculated and discussed, along with the Structure-Activity Relationships (SAR). This study thus highlights the importance of the acylation site and lipid-like fatty acid chain length that govern the antimicrobial activity of mannopyranoside-based SFAE.

Synthesis of novel benzo[d] imidazole bearing α-aminophosphonate and their antimicrobial evaluation

The antimicrobial activity of seven α-aminophosphonate derivatives was evaluated. These new compounds were synthesized via a one-pot reaction of the Kabachnik-Fields between 2-((1H-benzo[d]imidazol-2-yl)thio)acetohydrazide, aldehyde derivatives, and diethyl phosphite in the presence of magnesium triflate as a catalyst. The novel compounds are identified by analytical and spectroscopic techniques. The use of magnesium triflate as a catalyst revealed short reaction time (1 h), in 10 mol%.The activity of the new compounds was against the Gram-positive bacteria Bacillus cereus, and Staphylococcus aureus, as well as the Gram-negative bacteria Salmonella typhimurium, Escherichia coli, Pseudomonas aeruginose, and the fungus Candida albicans. The results indicated that most of the new compounds have moderate to high potency as antibacterial and antifungal agents. And the theoretical study confirmed that the compounds excel in binding with a more stable binding energy than the antibiotic penicillin, and this was confirmed by laboratory results. In the case of Escherichia coli ATCC® 25922™, only 5a and 5e displayed significant inhibitory activities equal to or greater than the reference drug. Most of the new compounds (5c–5 g) revealed high potency against Salmonella typhimurium ATCC® 14028™. The highest value is for 5d which has the high inhibitory activity against Cadida albicans.

In Silico and In Vitro Study of Isoquercitrin against Kidney Cancer and Inflammation by Triggering Potential Gene Targets.

Kidney cancer has emerged as a major medical problem in recent times. Multiple compounds are used to treat kidney cancer by triggering cancer-causing gene targets. For instance, isoquercitrin (quercetin-3-O-β-d-glucopyranoside) is frequently present in fruits, vegetables, medicinal herbs, and foods and drinks made from plants. Our previous study predicted using protein-protein interaction (PPI) and molecular docking analysis that the isoquercitrin compound can control kidney cancer and inflammation by triggering potential gene targets of IGF1R, PIK3CA, IL6, and PTGS2. So, the present study is about further in silico and in vitro validation. We performed molecular dynamic (MD) simulation, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, cytotoxicity assay, and RT-PCR and qRT-PCR validation. According to the MD simulation (250 ns), we found that IGF1R, PIK3CA, and PTGS2, except for IL6 gene targets, show stable binding energy with a stable complex with isoquercitrin. We also performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the final targets to determine their regulatory functions and signaling pathways. Furthermore, we checked the cytotoxicity effect of isoquercitrin (IQ) and found that 5 μg/mL and 10 μg/mL doses showed higher cell viability in a normal kidney cell line (HEK 293) and also inversely showed an inhibition of cell growth at 35% and 45%, respectively, in the kidney cancer cell line (A498). Lastly, the RT-PCR and qRT-PCR findings showed a significant decrease in PTGS2, PIK3CA, and IGF1R gene expression, except for IL6 expression, following dose-dependent treatments with IQ. Thus, we can conclude that isoquercitrin inhibits the expression of PTGS2, PIK3CA, and IGF1R gene targets, which in turn controls kidney cancer and inflammation.

In silico ADME and molecular simulation studies of pharmacological activities of phytoconstituents of Annona muricata (L.) Fruit

Annona muricata Lin is known for its ethnomedicinal uses as food, decoctions, or infusions to address various conditions like skin infections, fever, diabetes, insomnia, malaria, hypertension, nervous disorders, diarrhea, and cancer. The study aimed to analyze the phytochemicals such as acetogenins, alkaloids, cyclopeptides, and flavonoids, present in A. muricata fruit, evaluate their pharmacokinetics, and understand binding dynamics with key molecular targets relevant to human well-being. Results indicated a mix of high and low gastrointestinal absorption (GIA) among A. muricata phytochemicals, with some demonstrating blood-brain barrier (BBB) permeability. Molecular target prediction highlighted frequent interactions with Programmed cell death protein 4 (PDCD4). Protein-protein interaction analysis revealed central connectivity of tyrosinase (TYR), Tyrosine 3-monooxygenase (TH), interleukin 2 (IL2), and others. Molecular docking results identified Luteolin 3´7-di-O-glucoside with the highest binding affinity for PDCD4 (-7.65 kcal.mol-1), followed by Annonaine (-7.294 kcal.mol-1); meanwhile, Dexamethasone (standard compound) exhibited a binding affinity of -6.682 kcal.mol-1. Molecular dynamic simulation indicated a stable binding energy ΔGbind (Total) for the Annonaine - PDCD4 complex (-11.240 kcal.mol-1) and Dexamethasone - PDCD4 complex (-18.909 kcal.mol-1). In conclusion, this study suggests potential anticancer properties of A. muricata based on modulation of PDCD4 protein, influencing the CDK/Akt/STAT3 pathway. Further in vivo investigations are necessary to validate these findings.

Exploring potential therapeutics: Targeting dengue virus NS5 through molecular docking, ADMET profiling, and DFT analysis

Dengue fever is defined as a mosquito-borne Flaviviridae viral infection. It has become a huge public health issue worldwide. Dengue research has grown in recent years. The structure of the viral genome has been decoded, with the nonstructural protein NS5 acting as a possible target. The NS5 compound has an MTase domain contributing in RNA capping, adding an RdRp domain contributing in viral replication process. On the light of considering the NS5 as a possible medicinal target, this research included molecular docking studies executed using the Schrödinger suite software to examine 1412 compounds that were 80% similar to s-adenosyl-l-homocysteine,Top five compounds were chosen based on their sTable binding energies comparing to the reference. We next used the pkcsm web server to examine the ADMET characteristics of the top five ligands. Four compounds were identified as promising candidates for future therapeutic development. Finally, further analyzed using density functional theory approach.

Different functional groups of carbon dots influence the formation of protein crowns and pepsin characteristic in vitro digestion

Application of nanomaterials (NMs) in agriculture poses an ingestion risk to humans and may affect the digestive process. Different fates of NMs with differential charges in the gastrointestinal tract should be considered. In this study, the interaction between three carbon dots (CDs) carried with different functional groups (–NH2, –OH, and –COOH) and pepsin was analyzed through an in vitro digestion model. The results showed that CDs significantly reduced pepsin activity. Among them, CDs–NH2 had the greatest effect, following by CDs–OH, and CDs–COOH. Besides, molecular docking demonstrated the specific binding site of CDs to pepsin, while the most stable binding energy (–8.10 kcal/mol) was formed between CDs–NH2 and pepsin. Further, CDs formed a nanomaterial–protein crown structure with pepsin. The present study enriches the functional group properties of CDs in the digestion and provides new ideas for the potential human health of NMs.

Identification of promising inhibitors against breast cancer disease by targeting NUDIX hydrolase 5 (NUDT5) biomolecule

It is well documented that NUDT5 enzyme inhibition in breast cancer cell lines arrest cancer cells growth, invasiveness and migration. The NUDT5 enzyme enhances breast cancer aggressiveness and act as key regulator of oncogenic pathways. Similarly, the NUDT5 enzyme plays a primer role in ATP-dependent cellular processes and proliferation in breast cancer. Thus, the NUDT5 enzyme plays a profound contribution in promoting breast cancers carcinogenesis and could be an ideal target for anti-cancer drug discovery. In this work, LAS_51382001, LAS_51177972 and LAS_51380924 with binding energy of −12.64 kcal/mol, −11.59 kcal/mol and −10.01 kcal/mol, respectively were filtered as lead molecules. The control molecule binding energy was −10.87 kcal/mol. The system dynamics were found uniform in molecular dynamics simulation studies and observed with no major structural changes. Among the leads, the LAS_51177972 showed the most stable binding energy values. The MM-GBSA binding energy of the compound was −37.07 kcal/mol and MM-PBSA binding energy of −43.56 kcal/mol. Similarly, the compound revealed very stable WaterSwap absolute binding energy values; Bennett’s, TI and FEP energy of −36.2 kcal/mol, −36.13 kcal/mol and −36.58 kcal/mol, respectively. Similarly, the leads reported very favorable physicochemical properties, water solubility, pharmacokinetics, druglikeness and medicinal chemistry properties. In a nutshell, the compounds are potent in term of the current computational study however, need to be subjected to experimental studies.Communicated by Ramaswamy H. Sarma

In Vitro and In Vivo Effects of Synthesis Novel Phenoxyacetamide Derivatives as Potent Apoptotic Inducer against HepG2 Cells through PARP-1 Inhibition.

To discover potential cytotoxic agents, new semi-synthetic phenoxy acetamide derivatives, compound I and compound II, were synthesized, characterized, and screened for their cytotoxic activity against breast cancer (MCF-7) and liver cancer (HepG2) cell lines. The two compounds were more promising against HepG2 than the MCF-7 cell line according to IC50 values. When tested against the HepG2 cell line, compound I, and compound II both had significantly increased cytotoxic activity when compared to the reference medication 5-Fluorouracil (5-FU), with IC50 values of 1.43 M, 5.32 M, and 6.52 M for compound 1, 5-FU and compound II, respectively. Also, compound I displayed a degree of selectivity towards cancer cells compared to normal cells. Compound I significantly enhanced HepG2 total apoptotic cell death by about a 24.51-fold increase. According to cell cycle analysis, compound I induced the arrest of the cell cycle phases G1/S and blocked the progression of the HepG2 cells. Applying the RT-PCR technique achieved a highly significant upregulation in pro-apoptotic genes. The anti-apoptotic gene was significantly downregulated. There was an intrinsic and extrinsic pathway, but the intrinsic pathway was the dominant one. Tumor growth suppression as measured by tumor weight and volume and other hematological, biochemical, and histopathological analyses confirmed the efficacy of compound I as an anticancer agent in vivo examination. Finally, the molecular docking study revealed that compound I was properly docked inside the binding site of PARP-1 protein with stable binding energies and interactive binding modes. Therefore, compound I shows promise as a selective anti-cancer derivative for the treatment of liver cancer after more investigations and clinical studies. This selectivity is a favorable characteristic in the developing cytotoxic agents for cancer treatment, as it indicates a potential for reduced harm to health tissues.

Photocatalytic property of two dimensional heterostructure MoS2/WS2 for hydrogen evolution via water splitting; a first principles calculation

We investigated photocatalytic property of two dimensional heterostructure MoS2/WS2 by a first principles calculation. Firstly, we evaluated the energetic stability of different heterostructures by comparing combination energies of heterojunctions with those between adjacent layers in multilayer MoS2 or WS2 system after constructing nine heterostructures (MoS2)n/(WS2)m (n, m = 1, 2, 3). The subscripts n and m are the numbers of MoS2 or WS2 layers that are contained in the above heterostructures, respectively. The investigated heterostructures have all stable binding energy of about 0.2 eV. Secondly, we calculated band gap of every heterostructure in order to compare it with the oxidation/reduction level for water splitting. Among the considered nine structures, the heterostructure (MoS2)1/(WS2)1 is suitable for overall water splitting because it has a band gap of 1.70 eV and energy barrier of 0.21 eV for preventing recombination of electrons and holes generated by light irradiation. In addition, the heterostructure is also favorable to the evolution of hydrogen, as it has a low hydrogen desorption energy of 0.035 eV.

Synthesis, Characterization and Theoretical Investigations on the Molecular Structure, Electronic Property and anti-Trypanosomal Activity of Benzenesulphonamide-Based Carboxamide and Its Derivatives

Sulfonamide-based carboxamide drugs have multiple active sites that confers them with a variety of chemical and pharmacological activities. The combination of structural functionalities has been established to be vital in the drug discovery process. The synthesis of novel, nontoxic, cheap and effective anti-parasitic analogues is a trending aspect of pharmaceutical and medicinal chemistry research. In this research, the synthesis, characterization, and density functional theory (DFT) investigation of the reactivity and anti-trypanosomal simulation of benzenesulphonamide-based carboxamide derivatives was carried out for 2-[N-(benzenesulfonyl)-1-phenylformamido]-N-(4-nitrophenyl)acetamide(BPNA), 2-[N-(benzenesulfonyl)-1-phenylformamido]-N-(4-nitrophenyl)-3-phenylpropanamide (BPNPP), 2-[N-(benzenesulfonyl)-1-phenylformamido]-3-(1H-indol-2-yl)-N-(4-nitrophenyl)propenamide (BPINP) and 2-[N-(benzenesulfonyl)-1-phenylformamido]-4-methyl-N-(4-nitrophenyl)pentanamide (BPMNP) following an environmentally friendly zinc chloride catalyst mediated synthesis. The lower value of the HOMO-LUMO energy gap (2.9756 eV) observed for BPMNP indicated its higher chemical and biological activity. The global electrophilicity index (ω), which is related to chemical hardness and chemical potential in line with other global descriptors showed that the order of reactivity is BPMNP > BPINP > BPNPP > BPNA. The NBO analysis showed that σ → σ*, σ* →π*, π → π*, and π* → π* transitions were observed in all the compounds while σ → σ* and π* → π* showed the lowest and the highest stabilization energy, respectively. From the molecular docking analysis, BPMNP again, showed the most stable binding energy of − 9.6 kcal/mol and bond length of 1.99 Å, evidently performing better than the standard drug with binding energy and bond length of −7.6 kcal/mol and 2.89 Å, respectively. The binding energy obtained was observed to follow a decreasing order as thus; BPMNP > BPINP > BPNA > BPNPP which strongly indicates alkane-substituted benzenesulphonamide carboxamides especially BPINP and BPMNP possess potent curative properties against trypanosomiasis.

Atropine Is a Suppressor of Epithelial–Mesenchymal Transition (EMT) That Reduces Stemness in Drug-Resistant Breast Cancer Cells

Atropine (ATR) is extracted from a belladonna plant that belongs to a class of anticholinergic drugs and is therefore involved in the treatment of the overdose of cholinergic drugs or mushroom poisoning. It is a well-known blocker of muscarinic acetylcholine receptors (mAChRs) that are expressed in various tumor cells, including breast tumors from animal and human origin, but it has yet to be recommended as an anticancer drug. Our in silico docking analysis indicates that atropine has a roust virtual binding, with a stable binding energy, to two major signaling molecules involved in EMT regulation: E-cad and ZEB-2. For both, the gene and the protein expression level results show that atropine is an effective molecule in reducing epithelial–mesenchymal transition (EMT) and colony formation induced by TGF-B or carboplatin in both the mesenchymal-like cell line MDA-MB-231 and the epithelial-like cell line T47D. We conclude that atropine as a potential suppressor of EMT could be co-administrated with other chemotherapeutic drugs to reduce stemness in drug-resistant breast tumor cells.

Structural, functional, and molecular docking analyses of microbial cutinase enzymes against polyurethane monomers

Plastic waste is the biggest global problem in present times due to its constant bioaccumulation in the environment. During the last year, 367 Mt of plastics were produced in the world, of which 28.6 Mt correspond to polyurethane waste. Polyurethanes can be found in products such as adhesives, preservatives, and foams, and are often difficult to recycle. The fragmentation of plastic waste in the environment generates microplastics causing a long-term effect on our ecosystem. In search of its solution via bioremediation using enzymes, in our present study cutinase enzyme has been chosen, as it appears to be a novel candidate due to the wide variety of substrates it hydrolyzes and its presence in different microorganisms. According to physiochemical characteristics, it was found that microbial cutinase enzymes are majorly made up of aliphatic amino acids. A higher aliphatic index (more than 80) indicates the great thermostability of the enzyme. Moreover, the enzyme is found to be hydrophilic and structurally stable. The negative GRAVY value of the enzyme confirmed its stable interaction with water. It was also observed that all chosen protein models had an average of 91.10 % amino acids in the favorable regions of the Ramachandran plot. The studied microbial cutinase enzymes from both fungi Humicola insolens and actinobacterium Thermobifida fusca successfully coupled with the polyurethane resin monomers. The main interactions were found in the catalytic triad with bonds close to the urethane bonds of the ligand, in addition to having an average binding energy of − 6 kJ/mol. The interaction between the cutinases with the PUR resin as a ligand was found to be evident from our study with stable binding energies, which makes microbial cutinases potential enzymes for polyurethane waste bioremediation processes.

Identification of novel Plasmodium falciparum dihydroorotate dehydrogenase inhibitors for malaria using in silico studies

Malaria, that ancient infectious disease is considered a great health problem due to its highly infectious and mortality rates. The more harmful kind of malaria is Plasmodium falciparum (Pf), accounting for over 1M fatalities yearly; unfortunately, existing medication regimens are hampered by resistance, necessitating the identification of novel targets against plasmodium species. Since the malaria parasite cannot recover pyrimidines, it must rely on de novo production to survive. Dihydroorotate dehydrogenase (DHODH), which facilitates the rate-limiting phase of that process, is therefore an interesting antimalarial target. In this context, computational screening comprising pharmacophore mapping, molecular docking, MM-GBSA calculations, ADME filtering and molecular dynamics were performed in order to identify novel and powerful PfDHODH inhibitors. A pharmacophore hypothesis with seven features was created and tested on 2 million compounds from the enamine database. Docking, MM-GBSA calculations, and ADME revealed ten hits with strong binding affinities and potential, stable binding energy, and drug-like properties. The top three hits were confirmed further using molecular dynamics simulations, which revealed that three of them were stable for the whole 100 ns simulation time. Relying on these findings, we recommend that Z1481646084, Z24317941, and Z951873618 be submitted for experimental verification as promising antimalarial gents.

Probing the Action of Screened Anticancer Triazole–Tetrazole Derivatives Against COVID-19 Using Molecular Docking and DFT Investigations

Drugs are continuously being evaluated for novel therapeutic uses. The purpose of this work was to screen anticancer triazole/tetrazole derivatives for effectiveness against the SARS-CoV-2 main protease (Mpro). First, the chemical structures’ activity was derived from conceptual quantum chemical calculations. According to molecular docking analysis, the compounds scored good interactions against SAR-COV-2's Mpro, with binding energies extending from −8.21 to −8.97 kcal/mol. The docked complexes included various bindings with His41 and Cys145, both catalytic residues responsible for cleavage of the SARS-CoV-2 Mpro. Among the 4 studied compounds, TD3 exhibited the highest affinity by achieving the most stable binding energy and lowest value for the inhibition constant. Most striking was that TD3 not only formed strong bonds with the catalytic residues His41 and Cys145, but also captured the residues of the catalytic loop (Cys44 to Pro52), which flank the catalytic dyads in Mpro's active site. As a result, the studied triazole/tetrazole derivatives, notably TD3, must be reviewed as potent drugs that could be repurposed for SARS-CoV-2 treatment.

Potent antiviral activity of the extract of Elaeocarpus sylvestris against influenza A virus in vitro and in vivo

BackgroundElaeocarpus sylvestris (Lour.) Poir. (Elaeocarpaceae) belongs to a genus of tropical and semitropical evergreen trees, which has known biological activities such as antiviral and immunomodulatory activities. However, its antiviral potential against influenza virus infection remains unknown. PurposeIn this study, we investigated the antiviral activity of the 50% aqueous ethanolic extract of E. sylvestris (ESE) against influenza A virus (IAV) infection, which could lead to the development of novel phytomedicine to treat influenza virus infection. MethodsTo investigate the in vitro antiviral activity of ESE and its main ingredients, 1,​2,​3,​4,​6-​penta-​O-​galloyl-β-d-glucose (PGG) and geraniin (GE), the levels of viral RNAs, proteins, and infectious viral particles in IAV-infected MDCK cells were analyzed. Molecular docking analysis was performed to determine the binding energy of PGG and GE for IAV proteins. To investigate in vivo antiviral activity, IAV-infected mice were treated intranasally or intragastrically with ESE, PGG, or GE. ResultsESE and its gallate main ingredients (PGG and GE) strongly inhibited the production of viral RNAs, viral proteins, and infectious viral particles in vitro. Also through the viral attachment on cells, polymerase activity, signaling pathway, we revealed the ESE, PGG, and GE inhibit multiple steps of IAV replication. Molecular docking analysis revealed that PGG and GE could interact with 12 key viral proteins (M1, NP, NS1 effector domain (ED), NS1 RNA-binding domain (RBD), HA pocket A, HA receptor-binding domain (RBD), NA, PA, PB1, PB2 C-terminal domain, PB2 middle domain, and PB2 cap-binding domain) of IAV proteins with stable binding energy. Furthermore, intranasal administration of ESE, PGG, or GE protected mice from IAV-induced mortality and morbidity. Importantly, oral administration of ESE suppressed IAV replication and the expression of inflammatory cytokines such as IFN-γ, TNF-α, and IL-6 in the lungs to a large extent. ConclusionESE and its major components (PGG and PE) exhibited strong antiviral activity in multiple steps against IAV infection in silico, in vivo, and in vitro. Therefore, ESE could be used as a novel natural product derived therapeutic agent to treat influenza virus infection.

Pinocembrin Reduces Arthritic Symptoms in Mouse Model via Targeting Sox4 Signaling Molecules.

Rheumatoid arthritis (RA) is a chronic autoimmune, multifactorial, inflammatory disorder characterized by hyperplasia and infiltration of inflammatory cells at the synovial lining leading to destruction of cartilage and bone tissues. Pinocembrin (PCB) is a natural flavonoid extracted as a pure molecule from honey, propolis, and some plants. In this study, we evaluated the antiarthritic effect of PCB in adjuvant induced arthritis (AIA) mice. Treating the AIA mouse model with PCB reduced the arthritis symptoms/score, including edema size, extent of hind paw redness, abnormal movement, and holding inability. At the pathological level, PCB significantly decreased the joint erosion and percentages of infiltrated inflammatory cells. Biochemically, PCB interacts with the transcription factor, SRY-related HMG-box 4 (Sox4), and then modulates its dysregulated expression and the expression of Sox4/Stat3 signaling molecules in AIA mice. These molecules include tumor necrosis factor-α, nuclear transcription factor kappaB, and cyclooxygenase-2, besides the microRNAs; miR-132, miR-202-5p, and miR-7235, which are dysregulated in adjuvant-induced arthritis model relative to the control mice. The possible PCB interaction with Sox4 transcriptional protein was confirmed through molecular docking where three hydrogen bonds were formed at ARG and LYS residues at a stable binding energy of -4.72. Taken together, our data demonstrate that PCB could serve as a therapeutic drug in treatment of RA.

A Transcription Regulatory Sequence in the 5' Untranslated Region of SARS-CoV-2 Is Vital for Virus Replication with an Altered Evolutionary Pattern against Human Inhibitory MicroRNAs.

Our knowledge of the evolution and the role of untranslated region (UTR) in SARS-CoV-2 pathogenicity is very limited. Leader sequence, originated from UTR, is found at the 5′ ends of all encoded SARS-CoV-2 transcripts, highlighting its importance. Here, evolution of leader sequence was compared between human pathogenic and non-pathogenic coronaviruses. Then, profiling of microRNAs that can inactivate the key UTR regions of coronaviruses was carried out. A distinguished pattern of evolution in leader sequence of SARS-CoV-2 was found. Mining all available microRNA families against leader sequences of coronaviruses resulted in discovery of 39 microRNAs with a stable thermodynamic binding energy. Notably, SARS-CoV-2 had a lower binding stability against microRNAs. hsa-MIR-5004-3p was the only human microRNA able to target the leader sequence of SARS and to a lesser extent, also SARS-CoV-2. However, its binding stability decreased remarkably in SARS-COV-2. We found some plant microRNAs with low and stable binding energy against SARS-COV-2. Meta-analysis documented a significant (p < 0.01) decline in the expression of MIR-5004-3p after SARS-COV-2 infection in trachea, lung biopsy, and bronchial organoids as well as lung-derived Calu-3 and A549 cells. The paucity of the innate human inhibitory microRNAs to bind to leader sequence of SARS-CoV-2 can contribute to its high replication in infected human cells.