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Monoamine oxidase B (MAO-B) plays a pivotal role in the deamination process of monoamines, encompassing crucial neurotransmitters like dopamine and norepinephrine. The heightened interest in MAO-B inhibitors emerged after the revelation that this enzyme could potentially catalyze the formation of neurotoxic compounds from endogenous and exogenous sources. Computational screening methodologies serve as valuable tools in the quest for novel inhibitors, enhancing the efficiency of this pursuit. In this study, 43 acefylline derivatives were docked against the MAO-B enzyme for their chemotherapeutic potential and binding affinities that yielded GOLD fitness scores ranging from 33.21 to 75.22. Among them, five acefylline derivatives, namely, MAO-B14, MAO-B15, MAO-B16, MAO-B20, and MAO-B21, displayed binding affinities comparable to the both standards istradefylline and safinamide. These derivatives exhibited hydrogen-bonding interactions with key amino acids Phe167 and Ile197/198, suggesting their strong potential as MAO-B inhibitors. Finally, molecular dynamics (MD) simulations were conducted to evaluate the stability of the examined acefylline derivatives over time. The simulations demonstrated that among the examined acefylline derivatives and standards, MAO-B21 stands out as the most stable candidate. Density functional theory (DFT) studies were also performed to optimize the geometries of the ligands, and molecular docking was conducted to predict the orientations of the ligands within the binding cavity of the protein and evaluate their molecular interactions. These results were also validated by simulation-based binding free energies via the molecular mechanics energies combined with generalized Born and surface area solvation (MM-GBSA) method. However, it is necessary to conduct in vitro and in vivo experiments to confirm and validate these findings in future studies. [ABSTRACT FROM AUTHOR]

Context: Existing researches confirmed that β amyloid (Aβ) has a high affinity for the α7 nicotinic acetylcholine receptor (α7nAChR), associating closely to Alzheimer's disease. The majority of related studies focused on the experimental reports on the neuroprotective role of Aβ fragment (Aβx), however, with a lack of investigation into the most suitable binding region and mechanism of action between Aβ fragment and α7nAChR. In the study, we employed four Aβ1–42 fragments Aβx, Aβ1–16, Aβ10–16, Aβ12–28, and Aβ30–42, of which the first three were confirmed to play neuroprotective roles upon directly binding, to interact with α7nAChR. Methods: The protein–ligand docking server of CABS-DOCK was employed to obtain the α7nAChR-Aβx complexes. Only the top α7nAChR-Aβx complexes were used to perform all-atom GROMACS dynamics simulation in combination with Charmm36 force field, by which α7nAChR-Aβx interactions' dynamic behavior and specific locations of these different Aβx fragments were identified. MM-PBSA calculations were also done to estimate the binding free energies and the different contributions from the residues in the Aβx. Two distinct results for the first three and fourth Aβx fragments in binding site, strength, key residue, and orientation, account for why the fourth fails to play a neuroprotective role at the molecular level. [ABSTRACT FROM AUTHOR]

Benzofuran, 1,3,4-oxadiazole, and 1,2,4-triazole are privileged heterocyclic moieties that display the most promising and wide spectrum of biological activities against a wide variety of diseases. In the current study, benzofuran-1,3,4-oxadiazole BF1–BF7 and benzofuran-1,2,4-triazole compounds BF8–BF15 were tested against HCV NS5B RNA-dependent RNA polymerase (RdRp) utilizing structure-based screening via a computer-aided drug design (CADD) approach. A molecular docking approach was applied to evaluate the binding potential of benzofuran-appended 1,3,4-oxadiazole and 1,2,4-triazole BF1–BF15 molecules. Benzofuran-1,3,4-oxadiazole scaffolds BF1–BF7 showed lesser binding affinities (−12.63 to −14.04 Kcal/mol) than benzofuran-1,2,4-triazole scaffolds BF8–BF15 (−14.11 to −16.09 Kcal/mol) against the HCV NS5B enzyme. Molecular docking studies revealed the excellent binding affinity scores exhibited by benzofuran-1,2,4-triazole structural motifs BF-9 (−16.09 Kcal/mol), BF-12 (−15.75 Kcal/mol), and BF-13 (−15.82 Kcal/mol), respectively, which were comparatively better than benzofuran-based HCV NS5B inhibitors' standard reference drug Nesbuvir (−15.42 Kcal/mol). A molecular dynamics simulation assay was also conducted to obtain valuable insights about the enzyme–compounds interaction profile and structural stability, which indicated the strong intermolecular energies of the BF-9+NS5B complex and the BF-12+NS5B complex as per the MM-PBSA method, while the BF-12+NS5B complex was the most stable system as per the MM-GBSA calculation. The drug-likeness and ADMET studies of all the benzofuran-1,2,4-triazole derivatives BF8–BF15 revealed that these compounds possessed good medicinal chemistry profiles in agreement with all the evaluated parameters for being drugs. The molecular docking affinity scores, MM-PBSA/MM-GBSA and MD-simulation stability analysis, drug-likeness profiling, and ADMET study assessment indicated that N-4-fluorophenyl-S-linked benzofuran-1,2,4-triazole BF-12 could be a future promising anti-HCV NS5B RdRp inhibitor therapeutic drug candidate that has a structural agreement with the Nesbuvir standard reference drug. [ABSTRACT FROM AUTHOR]

Human tyrosinase (hTYR) is a key and rate-limiting enzyme along with human tyrosinase-related protein-1 (hTYRP1), which are among the most prominent targets of inhibiting hyper pigmentation and melanoma skin cancer. In the current in-silico computer-aided drug design (CADD) study, the structure-based screening of sixteen furan-1,3,4-oxadiazole tethered N-phenylacetamide structural motifs BF1–BF16 was carried out to assess their potential as hTYR and hTYRP1 inhibitors. The results revealed that the structural motifs BF1–BF16 showed higher binding affinities towards hTYR and hTYRP1 than the standard inhibitor kojic acid. The most bioactive lead furan-1,3,4-oxadiazoles BF4 and BF5 displayed stronger binding in affinities (−11.50 kcal/mol and −13.30 kcal/mol) than the standard drug kojic acid against hTYRP1 and hTYR enzymes, respectively. These were further confirmed by MM-GBSA and MM-PBSA binding energy computations. The stability studies involving the molecular dynamics simulations also provided stability insights into the binding of these compounds with the target enzymes, wherein it was found that they remain stable in the active sites during the 100 ns virtual simulation time. Moreover, the ADMET, as well as the medicinal properties of these novel furan-1,3,4-oxadiazole tethered N-phenylacetamide structural hybrids, also showed a good prospect. The excellent in-silico profiling of furan-1,3,4--oxadiazole structural motifs BF4 and BF5 provide a hypothetical gateway to use these compounds as potential hTYRP1 and hTYR inhibitors against melanogenesis. [ABSTRACT FROM AUTHOR]

Human Torovirus (HToV), a member of the Coronaviridae family, causes severe enteric diseases with no specific medication available. To develop novel preventative measures, we employed immunoinformatics techniques to design a multi-epitope-based subunit vaccine (HToV-MEV) triggering diverse immune responses. We selected non-allergenic, non-toxic, and antigenic epitopes from structural polyproteins, joined them with suitable linkers, and added an adjuvant 50S ribosomal L7/L12 peptide. The vaccine's solubility score of 0.903678 and physiochemical properties were found effective. Molecular dynamics simulations and free energy calculations revealed strong binding affinity for Toll-like receptor 3 (TLR-3), with a lowest energy score of −303.88, indicating high affinity. In-silico cloning and codon optimization showed significant production potential in E. coli. Immune simulations predicted a human immunological response. Our results are promising, but subsequent in vivo research is recommended. The HToV-MEV vaccine design demonstrates potential for preventing HToV-related diseases, and further investigation is warranted to explore its therapeutic applications. [Display omitted] • Designed a multi-epitope subunit vaccine (HToV-MEV) against Human Torovirus (HToV) to induce broad immune responses. • Selected non-allergenic, non-toxic and antigenic epitopes for enhanced effectiveness. • Molecular simulations showed strong binding to Toll-like receptor 3 (TLR-3) with an energy score of −303.88. • Codon optimization and in-silico cloning suggest efficient production in E. coli. • Immune simulations indicated strong human immune activation, supporting further in vivo studies. [ABSTRACT FROM AUTHOR]

In this work, BTEAC (benzyl triethylammonium chloride) was employed as a phase transfer catalyst in an improved synthesis (up to 88% yield) of S-alkylated bromobenzofuran-oxadiazole scaffolds BF1-9. These bromobenzofuran-oxadiazole structural hybrids BF1-9 were evaluated in vitro against anti-hepatocellular cancer (HepG2) cell line as well as for their in silico therapeutic potential against six key cancer targets, such as EGFR, PI3K, mTOR, GSK-3β, AKT, and Tubulin polymerization enzymes. Bromobenzofuran structural motifs BF-2, BF-5, and BF-6 displayed the best anti-cancer potential and with the least cell viabilities (12.72 ± 2.23%, 10.41 ± 0.66%, and 13.08 ± 1.08%), respectively, against HepG2 liver cancer cell line, and they also showed excellent molecular docking scores against EGFR, PI3K, mTOR, and Tubulin polymerization enzymes, which are major cancer targets. Bromobenzofuran-oxadiazoles BF-2, BF-5, and BF-6 displayed excellent binding affinities with the active sites of EGFR, PI3K, mTOR, and Tubulin polymerization enzymes in the molecular docking studies as well as in MMGBSA and MM-PBSA studies. The stable bindings of these structural hybrids BF-2, BF-5, and BF-6 with the enzyme targets EGFR and PI3K were further confirmed by molecular dynamic simulations. These investigations revealed that 2,5-dimethoxy-based bromobenzofuran-oxadiazole BF-5 (10.41 ± 0.66% cell viability) exhibited excellent cytotoxic therapeutic efficacy. Moreover, computational studies also suggested that the EGFR, PI3K, mTOR, and Tubulin polymerization enzymes were the probable targets of this BF-5 scaffold. In silico approaches, such as molecular docking, molecular dynamics simulations, and DFT studies, displayed excellent association with the experimental biological data of bromobenzofuran-oxadiazoles BF1-9. Thus, in silico and in vitro results anticipate that the synthesized bromobenzofuran-oxadiazole hybrid BF-5 possesses prominent anti-liver cancer inhibitory effects and can be used as lead for further investigation for anti-HepG2 liver cancer therapy. [ABSTRACT FROM AUTHOR]

The chemistry and biochemistry of carbohydrate esters are essential parts of biochemical and medicinal research. A group of methyl β-d-galactopyranoside (β-MGP, 1) derivatives was acylated with 3-bromobenzoyl chloride and 4-bromobenzoyl chloride in anhydrous N,N-dimethylformamide/triethylamine to obtain 6-O-substitution products, which were subsequently converted into 2,3,4-tri-O-acyl derivatives with different aliphatic and aromatic substituents. Spectroscopic and elemental data exploration of these derivatives confirmed their chemical structures. In vitro biological experiments against five bacteria and two fungi and the prediction of activity spectra for substances (PASS) revealed ascending antifungal and antibacterial activities compared with their antiviral activities. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) experiments were performed for two derivatives, 3 and 9, based on their antibacterial activities. Most of these derivatives showed >780% inhibition of fungal mycelial growth. Density functional theory (DFT) was used to calculate the chemical descriptors and thermodynamic properties, whereas molecular docking was performed against antibacterial drug targets, including PDB: 4QDI, 5A5E, 7D27, 1ZJI, 3K8E, and 2MRW, and antifungal drug targets, such as PDB: 1EA1 and 1AI9, to identify potential drug candidates for microbial pathogens. A 100 ns molecular dynamics simulation study revealed stable conformation and binding patterns in a stimulating environment by their uniform RMSD, RMSF, SASA, H-bond, and RoG profiles. In silico pharmacokinetic and quantitative structure–activity relationship (QSAR) calculations (pIC50 values 3.67~8.15) suggested that all the designed β-MGP derivatives exhibited promising results due to their improved kinetic properties with low aquatic and non-aquatic toxicities. These biological, structure–activity relationship (SAR) [lauroyl-(CH3(CH2)10CO-) group was found to have potential], and in silico computational studies revealed that the newly synthesized MGP derivatives are potential antibacterial/antifungal candidates and can serve as therapeutic targets for human and plant pathogens. [ABSTRACT FROM AUTHOR]

Carbohydrates derivatives played an important and vital role in a large part to design new potential drug against various pathogens, in medicinal chemistry. Also, monosaccharide derivatives are very useful in biological chemistry because monosaccharide binding agents were shown to possess antiviral, antibacterial, and antifungal activity towards HIV, Dengue coronaviruses, and many members of the family Enterobacteriaceae, including strains of Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, Shigella flexneri, and Enterobacter aerogenes. The present study was therefore interesting in identifying the binding affinity of a series of monosaccharides previously synthesized through their physicochemical and pharmacokinetic properties. These monosaccharides are derivatives of methyl-β-D-galactopyranoside (MGP) coupled to the protein deacetoxycephalosporin C synthase (DAOCS) of Streptomyces clavuligerus (1RXF). Molecular docking study against DAOCS proteins (PDB ID: 1RXF) was performed assess the antimicrobial activities of these derivatives along with antiviral prediction. The results of molecular docking studies showed that derivatives 8 and 10 both presented the highest score (-7.2 kcal/mol), reflecting their good binding affinity toward the active pocket of the pathogen S. clavuligerus (1RXF). They are found to be potent antimicrobial agents. These findings were further validated in dynamics (200 ns) milieu and intermolecular stability was evaluated via highly acceptable Molecular Mechanics Poisson-Boltzmann Surface Area (MMPB)/Molecular Mechanics/Generalized Born Surface Area (GBSA) binding free energies estimation methods. The dynamics of the complexes are highly stable with the strengthening of docked interactions as highlighted by MMPB/GBSA method (net binding energy < −40 kcal/mol). Density functional theory (DFT) calculations were carried out on the derivatives of MGP in order to determine the partial atomic charges, electronic energies, enthalpies, entropies and polarizability, at the B3LYP/3-21G level. The in silico ADMET prediction carried out provided access to the bioactivity and toxicity parameters which established that most of the different ligands designed are safe to use as drugs. This in silico study provided an overall view of the possible pharmacological and therapeutic profile of MGP derivatives. It therefore, paved the way for the discovery of promising next-generation drugs against pathogenic microbes. [ABSTRACT FROM AUTHOR]

An efficient pathway was disclosed for the synthesis of 3-chloro-6-nitro-1H-indazole derivatives by 1,3-dipolar cycloaddition on dipolarophile compounds 2 and 3. Faced the problem of separation of two regioisomers, a click chemistry method has allowed us to obtain regioisomers of triazole-1,4 with good yields from 82 to 90% were employed. Also, the antileishmanial biological potency of the compounds was achieved using an MTT assay that reported compound 13 as a promising growth inhibitor of Leishmania major. Molecular docking demonstrated highly stable binding with the Leishmania trypanothione reductase enzyme and produced a network of hydrophobic and hydrophilic interactions. Molecular dynamics simulations were performed for TryR-13 complex to understand its structural and intermolecular affinity stability in a biological environment. The studied complex remained in good equilibrium with a structure deviation of ~1-3Å. MM/GBSA binding free energies illustrated the high stability of TryR-13 complex. The studied compounds are promising leads for structural optimisation to enhance the antileishmanial activity. [ABSTRACT FROM AUTHOR]

The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is one of the optimum targets for antiviral drug design and development. The hydroxyl groups of cytidine structures were modified with different aliphatic and aromatic groups to obtain 5´-O-acyl and 2´,3´-di-O-acyl derivatives, and then, these derivatives were employed in molecular modeling, antiviral prediction, molecular docking, molecular dynamics, pharmacological and POM studies. Density functional theory (DFT) at the B3LYP/6-31G++ level analyzed biochemical behavior and molecular electrostatic potential (MESP) of the modified cytidine derivatives. The antiviral parameters of the mutated derivatives revealed promising drug properties compared with those of standard antiviral drugs. Molecular docking has determined binding affinities and interactions between the cytidine derivatives and SARS-CoV-2 RdRp. The modified derivatives strongly interacted with prime Pro620 and Lys621 residues. The binding conformation and interactions stability were investigated by 200 ns of molecular dynamics simulations and predicted the compounds to firmly dock inside the RdRp binding pocket. Interestingly, the binding residues of the derivatives were revealed in high equilibrium showing an enhanced binding affinity for the molecules. Intermolecular interactions are dominated by both Van der Waals and electrostatic energies. Finally, the pharmacokinetic characterization of the optimized inhibitors confirmed the safety of derivatives due to their improved kinetic properties. The selected cytidine derivatives can be suggested as potential inhibitors against SARS-CoV-2. The POM Theory supports the hypothesis above by confirming the existence of an antiviral (Oδ-—O'δ-) pharmacophore site of Hits. [ABSTRACT FROM AUTHOR]

This study reports the synthesis of two new hydrazide derivatives, namely, (E)‐N′‐(4‐ bromobenzylidene)−2‐(4‐isobutylphenyl)propanehydrazide (4a) and (E)‐N′‐benzylidene‐2‐(4‐isobutylphenyl)propanehydrazide (4b), respectively. The compounds were synthesized by the reaction of benzaldehyde with Ibuprofen acid hydrazide. Their structures were confirmed by X‐ray crystallography. To try to do a more detailed investigation, computational studies including Hirshfeld surface analyses, energy frameworks, density functional theory (DFT) optimizations, frontier orbital analyses, molecular electrostatic potential analyses, and natural bond orbital analyses of the studied compounds are performed. Moreover, molecular docking and dynamics simulations of complexes of the compounds with the cyclooxygenase‐2 (COX‐2) enzyme were performed to determine the anti‐inflammatory potential of the compounds. These analyses predicted the compounds to show maximum chemical interactions and be dynamically stable during simulation time. Furthermore, estimation of binding free energies confirmed the high binding affinity of the compounds for the COX‐2 enzyme. [ABSTRACT FROM AUTHOR]

The Rift Valley fever virus (RVFV) is a zoonotic arbovirus and pathogenic to both humans and animals. Currently, no proven effective RVFV drugs or licensed vaccine are available for human or animal use. Hence, there is an urgent need to develop effective treatment options to control this viral infection. RVFV glycoprotein N (GN), glycoprotein C (GC), and nucleocapsid (N) proteins are attractive antiviral drug targets due to their critical roles in RVFV replication. In present study, an integrated docking-based virtual screening of more than 6000 phytochemicals with known antiviral activities against these conserved RVFV proteins was conducted. The top five hit compounds, calyxin C, calyxin D, calyxin J, gericudranins A, and blepharocalyxin C displayed optimal binding against all three target proteins. Moreover, multiple parameters from the molecular dynamics (MD) simulations and MM/GBSA analysis confirmed the stability of protein–ligand complexes and revealed that these compounds may act as potential pan-inhibitors of RVFV replication. Our computational analyses may contribute toward the development of promising effective drugs against RVFV infection. [ABSTRACT FROM AUTHOR]

Whipple's disease is caused by T. whipplei, a Gram-positive pathogenic bacterium. It is considered a persistent infection affecting various organs, more likely to infect males. There is currently no licensed vaccination available for Whipple's disease; thus, the development of a chimeric peptide-based vaccine against T. whipplei has the potential to be tremendously beneficial in preventing Whipple's disease in the future. The present study aimed to apply modern computational approaches to generate a multi-epitope-based vaccine that expresses antigenic determinants prioritized from the core proteome of two T. whipplei whole proteomes. Using an integrated computational approach, four immunodominant epitopes were found from two extracellular proteins. Combined, these epitopes covered 89.03% of the global population. The shortlisted epitopes exhibited a strong binding affinity for the B- and T-cell reference set of alleles, high antigenicity score, nonallergenic nature, high solubility, nontoxicity, and excellent binders of DRB1*0101. Through the use of appropriate linkers and adjuvation with a suitable adjuvant molecule, the epitopes were designed into a chimeric vaccine. An adjuvant was linked to the connected epitopes to boost immunogenicity and efficiently engage both innate and adaptive immunity. The physiochemical properties of the vaccine were observed favorable, leading toward the 3D modeling of the construct. Furthermore, the vaccine's binding confirmation to the TLR-4 critical innate immune receptor was also determined using molecular docking and molecular dynamics (MD) simulations, which shows that the vaccine has a strong binding affinity for TLR4 (−29.4452 kcal/mol in MM-GBSA and −42.3229 kcal/mol in MM-PBSA). Overall, the vaccine described here has a promising potential for eliciting protective and targeted immunogenicity, subject to further experimental testing. [ABSTRACT FROM AUTHOR]

The present analysis has been performed in the wet‐lab and computational environments. First, the synthesis of the latest heterocyclic compounds containing the alkyl organic compound fragment of acetate and glycine acid were obtained and then their crystal structure and biological activity were studied. (Z)‐ethyl‐2‐(3‐oxo‐1,3‐diphenylprop‐1‐enylamino) acetate (1) was initially retrieved on the supported reaction of dibenzene gas with glycine alkyl organic compound‐complex within the presence of Y(OTF)3 catalyst in liquid medium. At an identical time, ethyl‐3,5‐diphenyl‐1H‐pyrrole‐2‐carboxylate (2) was synthesized from the interaction of amino alkane with tert‐BuOK in the presence of tert‐BuOH/DMFA solvent. The structure of the latest compounds has been studied by 1H, 13C NMR. Additionally, the crystal structure of ethyl‐3,5‐diphenyl‐1H‐pyrrole‐2‐carboxylate (2) is conferred. Moreover, computational drug‐likeness and pharmacokinetics indicated the compounds' good drug‐like molecules and friendly pharmacokinetics, making the compound valuable candidates to be explored for additional structural modification to act as a potential inhibitor of AChE and α‐glycosidase enzymes. [ABSTRACT FROM AUTHOR]

Hantaviruses are negative-sense, enveloped, single-stranded RNA viruses of the family Hantaviridae. In recent years, rodent-borne hantaviruses have emerged as novel zoonotic viruses posing a substantial health issue and socioeconomic burden. In the current research, a reverse vaccinology approach was applied to design a multi-epitope-based vaccine against hantavirus. A set of 340 experimentally reported epitopes were retrieved from Virus Pathogen Database and Analysis Resource (ViPR) and subjected to different analyses such as antigenicity, allergenicity, solubility, IFN gamma, toxicity, and virulent checks. Finally, 10 epitopes which cleared all the filters used were linked with each other through specific GPGPG linkers to construct a multi-antigenic epitope vaccine. The designed vaccine was then joined to three different adjuvants—TLR4-agonist adjuvant, β-defensin, and 50S ribosomal protein L7/L12—using an EAAAK linker to boost up immune-stimulating responses and check the potency of vaccine with each adjuvant. The designed vaccine structures were modelled and subjected to error refinement and disulphide engineering to enhance their stability. To understand the vaccine binding affinity with immune cell receptors, molecular docking was performed between the designed vaccines and TLR4; the docked complex with a low level of global energy was then subjected to molecular dynamics simulations to validate the docking results and dynamic behaviour. The docking binding energy of vaccines with TLR4 is −29.63 kcal/mol (TLR4-agonist), −3.41 kcal/mol (β-defensin), and −11.03 kcal/mol (50S ribosomal protein L7/L12). The systems dynamics revealed all three systems to be highly stable with a root-mean-square deviation (RMSD) value within 3 Å. To test docking predictions and determine dominant interaction energies, binding free energies of vaccine(s)–TLR4 complexes were calculated. The net binding energy of the systems was as follows: TLR4-agonist vaccine with TLR4 (MM–GBSA, −1628.47 kcal/mol and MM–PBSA, −37.75 kcal/mol); 50S ribosomal protein L7/L12 vaccine with TLR4 complex (MM–GBSA, −194.62 kcal/mol and MM–PBSA, −150.67 kcal/mol); β-defensin vaccine with TLR4 complex (MM–GBSA, −9.80 kcal/mol and MM–PBSA, −42.34 kcal/mol). Finally, these findings may aid experimental vaccinologists in developing a very potent hantavirus vaccine. [ABSTRACT FROM AUTHOR]

Porphyromonas gingivalis is a Gram-negative pathogenic bacterium associated with chronic periodontitis. The development of a chimeric peptide-based vaccine targeting this pathogen could be highly beneficial in preventing oral bone loss as well as other severe gum diseases. We applied a computational framework to design a multi-epitope-based vaccine candidate against P. gingivalis. The vaccine comprises epitopes from subunit proteins prioritized from the P. gingivalis reference strain (P. gingivalis ATCC 33277) using several reported vaccine properties. Protein-based subunit vaccines were prioritized through genomics techniques. Epitope prediction was performed using immunoinformatic servers and tools. Molecular modeling approaches were used to build a putative three-dimensional structure of the vaccine to understand its interactions with host immune cells through biophysical techniques such as molecular docking simulation studies and binding free energy methods. Genome subtraction identified 18 vaccine targets: six outer-membrane, nine cytoplasmic membrane-, one periplasmic, and two extracellular proteins. These proteins passed different vaccine checks required for the successful development of a vaccine candidate. The shortlisted proteins were subjected to immunoinformatic analysis to map B-cell derived T-cell epitopes, and antigenic, water-soluble, non-toxic, and good binders of DRB1*0101 were selected. The epitopes were then modeled into a multi-epitope peptide vaccine construct (linked epitopes plus adjuvant) to enhance immunogenicity and effectively engage both innate and adaptive immunity. Further, the molecular docking approach was used to determine the binding conformation of the vaccine to TLR2 innate immune receptor. Molecular dynamics simulations and binding free energy calculations of the vaccine–TLR2 complex were performed to highlight key intermolecular binding energies. Findings of this study will be useful for vaccine developers to design an effective vaccine for chronic periodontitis pathogens, specifically P. gingivalis. [ABSTRACT FROM AUTHOR]

Humans are a major reservoir of the hepatitis B virus (HBV), therefore promising treatment and control vaccination strategies are needed to eradicate the virus. Though promising drugs and vaccines are available against HBV, still efforts are required to enrich the therapy options. Herein, the HBV assembly protein was explored to identify novel targets for future use against HBV. Computer-aided drug designing and immune-informatics techniques were employed for the identification of putative inhibitors and vaccine ensemble against HBV using capsid assembly protein. The identified drug molecule binds with high affinity to the active pocket of the protein, and several epitopes are scanned in the protein sequence. The drug molecule, besides being a good putative inhibitor, has acceptable drug-like properties. A multi-epitope vaccine is also constructed to overcome the limitations of weakly immunogenic epitopes. In contrast to the MHC II level, the set of predicted epitopes has been recognized to interact with significant numbers of HLA alleles of MHC I. Selected epitopes are extremely virulent, antigenic, nontoxic, nonallergic, have suitable affinity to bind with the prevailing DRB*0101 allele, and also spectacle 86% mediocre population coverage. A multi-epitope peptide-based vaccine chimera having 73 amino acids was designed. It emerged as substantially immunogenic, thermally stable, robust in producing cellular as well as humoral immune responses, and had competent physicochemical properties to analyze in vitro and in vivo studies. The capsid assembly protein is a in more stable nature in the presence of the drug molecule compared to the TLR3 receptor in the vaccine presence. These particulars were confirmed by exposing the docked molecules to absolute and relative binding free energy approaches of MMGBSA/PBSA. The purpose to investigate the interactions between the vaccine and a representative TLR3 immune receptor can reveal the intermolecular affinity and possible presentation mechanism of the vaccine by TLR3 to the host immune system. It was revealed that the vaccine is showing a very good affinity of binding for the TLR3 and forming a network of hydrophobic and hydrophilic interactions. Overall, the findings of this study are promising and might be useful for further experimental validations. [ABSTRACT FROM AUTHOR]

Background: A recent COVID-19 pandemic has resulted in a large death toll rate globally and even no cure or vaccine has been successfully employed to combat this disease. Patients have been reported with multi-organ dysfunction along with acute respiratory distress syndrome which implies a critical situation for patients and made them difficult to breathe and survive. Moreover, pathology of COVID-19 is also related to cytokine storm which indicates the elevated levels of interleukin (IL)-1, IL-6, IL-12, and IL-18 along with tumor necrosis factor (TNF)-α. Among them, the proinflammatory cytokine IL-6 has been reported to be induced via binding of severe acute respiratory syndrome coronavirus 2 (SARS)-CoV-2 to the host receptors. Methodology: Interleukin-6 blockade has been proposed to constitute novel therapeutics against COVID-19. Thus, in this study, 15 phytocompounds with known antiviral activity have been subjected to test for their inhibitory effect on IL-6. Based on the affinity prediction, top 3 compounds (isoorientin, lupeol, and andrographolide) with best scores were selected for 50 ns molecular dynamics simulation and MMGB/PBSA binding free energy analysis. Results: Three phytocompounds including isoorientin, lupeol, and andrographolide have shown strong interactions with the targeted protein IL-6 with least binding energies (−7.1 to −7.7 kcal/mol). Drug-likeness and ADMET profiles of prioritized phytocompounds are also very prominsing and can be further tested to be potential IL-6 blockers and thus benficial for COVID-19 treatment. The moelcular dynamics simulation couple with MMGB/PBSA binding free energy estimation validated conformational stability of the ligands and stronger intermolecular binding. The mean RMSD of the complexes is as: IL6-isoorientin complex (3.97 Å ± 0.77), IL6-lupeol (3.97 Å ± 0.76), and IL6-andrographolide complex (3.96 Å ± 0.77). In addition, the stability observation was affirmed by compounds mean RMSD: isoorientin (0.72 Å ± 0.32), lupeol (mean 0.38 Å ± 0.08), and andrographolide (1.09 Å ± 0.49). A similar strong agreement on systems stability was unraveled by MMGB/PBSA that found net binding net ~ −20 kcal/mol for the complexes dominated by van der Waal interaction energy. Conclusion: It has been predicted that proposing potential IL-6 inhibitors with less side effects can help critical COVID-19 patients because it may control the cytokine storm, a major responsible factor of its pathogenesis. In this study, 3 potential phytocompounds have been proposed to have inhibitory effect on IL-6 that can be tested as potential therapeutic options against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Mycobacteroides abscessus (Previously Mycobacterium abscessus) is an emerging microorganism of the newly defined genera Mycobacteroides that causes mainly skin and tissue diseases in humans. The recent availability of total 34 fully sequenced genomes of different strains belonging to this species has provided an opportunity to utilize this genomics data to gain novel insights and guide the development of specific antimicrobial therapies. In the present study, we collected collectively 34 complete genome sequences of M. abscessus from the NCBI GenBank database. Pangenome analysis was conducted on these genomes to understand the genetic diversity and to obtain proteins associated with its core genome. These core proteins were then subjected to various subtractive filters to identify potential antigenic targets that were subjected to multi-epitope vaccine design. Our analysis projected the open pangenome of M. abscessus containing 3443 core genes. After applying various stepwise filtration steps on the core proteins, a total of four potential antigenic targets were identified. Utilizing their constituent CD4 and CD8 T-cell epitopes, a multi-epitope based subunit vaccine was computationally designed. Sequence-based analysis as well as structural characterization revealed the immunological effectiveness of this designed vaccine. Further molecular docking, molecular dynamics simulation and binding free energy estimation with Toll-like receptor 2 indicated strong structural associations of the vaccine with the immune receptor. The promising results are encouraging and need to be validated by additional wet laboratory studies for confirmation. [ABSTRACT FROM AUTHOR]

The emergence and dissemination of pan drug resistant clones of Klebsiella pneumoniae are great threat to public health. In this regard new therapeutic targets must be highlighted to pave the path for novel drug discovery and development. Subtractive proteomic pipeline brought forth UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase (LpxC), a Zn+2 dependent cytoplasmic metalloprotein and catalyze the rate limiting deacetylation step of lipid A biosynthesis pathway. Primary sequence analysis followed by 3-dimensional (3-D) structure elucidation of the protein led to the detection of K. pneumoniae LpxC (KpLpxC) topology distinct from its orthologous counterparts in other bacterial species. Molecular docking study of the protein recognized receptor antagonist compound 106, a uridine-based LpxC inhibitory compound, as a ligand best able to fit the binding pocket with a Gold Score of 67.53. Molecular dynamics simulation of docked KpLpxC revealed an alternate binding pattern of ligand in the active site. The ligand tail exhibited preferred binding to the domain I residues as opposed to the substrate binding hydrophobic channel of subdomain II, usually targeted by inhibitory compounds. Comparison with the undocked KpLpxC system demonstrated ligand induced high conformational changes in the hydrophobic channel of subdomain II in KpLpxC. Hence, ligand exerted its inhibitory potential by rendering the channel unstable for substrate binding. [ABSTRACT FROM AUTHOR]

d -Alanine- d -alanine ligase (Ddl), an enzyme that catalyzes the d -ala- d -ala dipeptide formation in UDPMurNAc pentapeptide, is a part of peptidoglycan biosynthesis machinery. Inhibition of enzyme leads to bacterial growth arrest making it a viable and attractive target for screening of potent antibacterial drugs. Combination of virtual screening, molecular docking, in silico pharmacokinetics, molecular dynamics (MD) simulation, and binding free energy calculations based on Molecular Mechanics Generalized Born and Surface Area (MMGBSA) and WaterSwap were applied in the current framework for the detailed analysis of potent natural inhibitors against Ddl enzyme. Comparative molecular docking supported with computational druglikeness revealed compound-331 (6-(4-((3-methoxyphenylsulfonamido) methyl) phenyl)-2-methylnicotinamide) as the best docked inhibitor. The inhibitor has Genetic Optimization for Ligand Docking (GOLD) fitness score of 84.2 and AutoDock Vina binding energy of −7.2 kcal/mol. The inhibitor exhibited to have a better druglikeness by adhering to Lipinski rule of five, Ghose rule, Veber filter, Egan filter, and Muegge filter in contrast to d -cycloserine, which violates Ghose and Muegge rule. MD simulation unravels that in complex over the course of 100-ns, the enzyme remained highly stable with mean Root Mean Square Deviation (RMSD) of 1.4 Å when compared to an undocked structure having RMSD of 1.6 Å. Root Mean Square Fluctuation (RMSF) predicted stable behaviour of the active site residues in both undocked and docked system with average RMSD values of 1.2 Å and 0.7 Å, respectively. Radial Distribution Function (RDF) and Axial Frequency Distribution (AFD) demonstrated Lys176 and Trp177 as critical residues of enzyme for binding, anchoring and bridging strong hydrogen and hydrophobic contacts between enzyme and the inhibitor. The estimated MMGBSA based binding free energy for the complex is −47.36 kcal/mol, signifying its stable nature. WaterSwap further indicated a worthy agreement on the affinity of inhibitor towards enzyme active pocket. This newly discovered natural inhibitor might serve a parent structure for the development of more potent derivatives with encouraging biological activity. [ABSTRACT FROM AUTHOR]

MurF ligase catalyzes the final cytoplasmic step of bacterial peptidoglycan biosynthesis and, as such, is a validated target for therapeutic intervention. Herein, we performed molecular docking to identify putative inhibitors of Acinetobacter baumannii MurF ( Ab MurF). Based on comparative docking analysis, compound 114 (ethyl pyridine substituted 3-cyanothiophene) was predicted to potentially be the most active ligand. Computational pharmacokinetic characterization of drug-likeness of the compound showed it to fulfil all the parameters of Muegge and the MDDR rule. A molecular dynamic simulation of 114 indicated the complex to be stable on the basis of an average root mean square deviation (RMSD) value of 2.09 Å for the ligand. The stability of the complex was further supported by root mean square fluctuation (RMSF), beta factor and radius of gyration values. Analyzing the complex using radial distribution function (RDF) and a novel analytical tool termed the axial frequency distribution (AFD) illustrated that after simulation the ligand is positioned in close vicinity of the protein active site where Thr42 and Asp43 participate in hydrogen bonding and stabilization of the complex. Binding free energy calculations based on the Poisson-Boltzmann or Generalized–Born Surface Area Continuum Solvation (MM(PB/GB)SA) method indicated the van der Waals contribution to the overall binding energy of the complex to be dominant along with electrostatic contributions involving the hot spot amino acids from the protein active site. The present results indicate that the screened compound 114 may act as a parent structure for designing potent derivatives against Ab MurF in specific and MurF of other bacterial pathogens in general. [ABSTRACT FROM AUTHOR]

In the present work, we describe the extraction of a natural product namely 1,4,9,9-tetramethyloctahydro-4,7-(epoxymethano)azulen-5(1 H)-one, and its structure was confirmed by single crystal X-ray diffraction analysis. The conformations of the 5-, 6-, and 7-membered rings in the title compound, C 15 H 24 O 2 , have been probed by a Cremer-Pople puckering analysis. C—H···O hydrogen bonds generate chains in the crystal that stretch along the c -axis direction. The Hirshfeld surface analysis method was used to stabilize the crystal packing of the natural compound. Accompanied by experimental studies, quantum chemical calculations were also performed to compare the structural elucidation and the results of these geometrical parameters exhibited excellent agreement. The compound was also docked with several drug targets of the SARS-CoV-2 virus and found to show the best binding with the main protease enzyme, having a binding energy of −12.31 kcal/mol and interacting with His41 and Cys145 residues. The dynamic stability deciphered the complex to be stable with an average RMSD of 3.8 Å. The compound dynamics with the enzyme showed the compound conformation to be highly stable. The intermolecular binding free energy determined the compound-main protease enzyme to show high interaction energy of < 40 kcal/mol. Together, these studies demonstrate the compound to be a lead structure against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Hendra virus (HeV) belongs to the paramyxoviridae family of viruses which is associated with the respiratory distress, neurological illness, and potential fatality of the affected individuals. So far, no competitive approved therapeutic substance is available for HeV. For that reason, the current research work was conducted to propose some novel compounds, by adopting a Computer Aided Drug Discovery approach, which could be used to combat HeV. The G attachment Glycoprotein (Ggp) of HeV was selected to achieve the primary objective of this study, as this protein makes the entry of HeV possible in the host cells. Briefly, a library of 6000 antiviral compounds was screened for potential drug-like properties, followed by the molecular docking of short-listed compounds with the Protein Data Bank (PDB) structure of Ggp. Docked complexes of top two hits, having maximum binding affinities with the active sites of Ggp, were further considered for molecular dynamic simulations of 200 ns to elucidate the results of molecular docking analysis. MD simulations and Molecular Mechanics Energies combined with the Generalized Born and Surface Area (MMGBSA) or Poisson–Boltzmann and Surface Area (MMPBSA) revealed that both docked complexes are stable in nature. Furthermore, the same methodology was used between lead compounds and HeV Ggp in complex with its functional receptor in human, Ephrin-B2. Surprisingly, no major differences were found in the results, which demonstrates that our identified compounds can also perform their action even when the Ggp is attached to the Ephrin-B2 ligand. Therefore, in light of all of these results, we strongly suggest that compounds (S)-5-(benzylcarbamoyl)-1-(2-(4-methyl-2-phenylpiperazin-1-yl)-2-oxoethyl)-6-oxo-3,6-dihydropyridin-1-ium-3-ide and 5-(cyclohexylcarbamoyl)-1-(2-((2-(3-fluorophenyl)-2-methylpropyl)amino)-2-oxoethyl)-6-oxo-3,6-dihydropyridin-1-ium-3-ide could be considered as potential therapeutic agents against HeV; however, further in vitro and in vivo experiments are required to validate this study. [ABSTRACT FROM AUTHOR]

• Single crystal XRD of novel synthesized pyrimidopyrimidine compound showed that molecules are connected by N H ⋯ O, O H ⋯ S, C H ⋯ S, C H ⋯ Cl, C H ⋯ N, π ⋯ π, and C Cl ⋯ π interactions.. • Hirshfeld surface analysis inferred that H ⋯ H, H ⋯ S, H ⋯ Cl and H ⋯ C contacts are important for stabilization of the supramolecular assembly. • Interaction energy calculations showed that dispersion energy played prominent role for stabilization of the supramolecular assembly. • Computational study results are consistent with the corresponding ones of single crystal XRD. • Molecular docking study showed that the compound is one of the potential candidate of the anti-diabetic drugs. We studied the three-component condensation of 2-chloraldehyde, acetophenone, and thiourea in conjunction with HCl, resulting in the formation of a new compound: 4,5-bis(2-chlorophenyl)-8a-phenylhexahydropyrimido[4,5-d]pyrimidine-2,7(1 H ,3 H)-dithione (CPPD). The compound's structure was affirmed via X-ray diffraction study. The asymmetric unit contained two molecules that were independent relative to crystallography and an ethanol solvent. The difference between independent molecules was explored by dihedral angles between similar rings in both molecular. The difference between molecules was further explored by molecular overlay plot. The supramolecular assembly was supported via diverse intermolecular interactions which were studied through the use of Hirshfeld surface analysis. Electronic structure computations were carried out at the ωb97xd/tzvp level. Natural bonding orbital (NBO), and FMO study reveal reactivity and charge transfer mechanisms within the compound. Furthermore, the nature of bonding in the present molecule is characterized through quantum theory of atoms in molecules (QTAIM), ELF, and LOL studies. Ab-initio molecular dynamic (AIMD) revealed the kinetic and thermodynamic stability at 300 K. The DFT results have excellent correlation with experimental data. The molecular docking and molecular dynamics simulation further revealed the compound to get deep access in the active pocket of type 2 anti-diabetes GLUT4 protein. This was validated by the stable dynamics as demonstrated by the uniform behavior of the root mean square deviation (RMSD) plot. The root mean square fluctuation (RMSF) also showed stable interactions with amino acids in the presence of the compound. Further, simulation trajectories on the basis of binding free energies indicate the significant role of van der Waals force in the formation of the intermolecular docked complex. This concluded the compound might be a potent structure for the development of anti-diabetic compounds. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Protein-ligand docking, and molecular dynamics (MD) simulations were used to characterize AGEs-RAGE interactions. • MD simulations assessed the stability of AGEs-RAGE complexes, and identified essential AGEs-RAGE complex. • Insights into structural movements, stability, and conformational dynamics of the complexes were obtained through MD simulations. • The research provides new molecular insights into AGEs-RAGE complex formation related to diabetes and its complications. • The findings facilitate the drug discovery process by elucidating mechanisms of AGEs-RAGE interactions. Diabetes mellitus is a global health challenge, ranking third among the mortality rates globally. Diabetic-mediated Advanced glycation end products (AGEs) associated with Receptor for Advanced Glycation End-products (RAGE) contribute to chronic diabetes and its complications, inflammatory, cancer, and neurodegenerative disorders. The information behind the binding mechanisms between AGEs-RAGE complexes remains elusive. In the current study, we used advanced computational approaches to reveal the intramolecular interactions of AGEs-RAGE which leads to multiple diseases. We have characterized AGEs-RAGE interactions by protein–ligand docking and molecular dynamic (MD) simulations were further conducted to evaluate the AGEs-RAGE complex stability. Subsequently, several residues emerged as pivotal in AGEs-RAGE complex formation. Further, MD simulation provides valuable insights into structural movements, stability, and conformational dynamics of protein–ligand complexes. Our findings underscore new insights into molecular mechanisms of AGEs-RAGE complex formation in diabetes and its related complications and the ease of the drug discovery process. [ABSTRACT FROM AUTHOR]

Yersinia pestis is responsible for plague and major pandemics in Asia and Europe. This bacterium has shown resistance to an array of drugs commonly used for the treatment of plague. Therefore, effective therapeutics measurements, such as designing a vaccine that can effectively and safely prevent Y. pestis infection, are of high interest. To fast-track vaccine development against Yersinia pestis, herein, proteome-wide vaccine target annotation was performed, and structural vaccinology-assisted epitopes were predicted. Among the total 3909 proteins, only 5 (rstB, YPO2385, hmuR, flaA1a, and psaB) were shortlisted as essential vaccine targets. These targets were then subjected to multi-epitope vaccine design using different linkers. EAAK, AAY, and GPGPG as linkers were used to link CTL, HTL, and B-cell epitopes, and an adjuvant (beta defensin) was also added at the N-terminal of the MEVC. Physiochemical characterization, such as determination of the instability index, theoretical pI, half-life, aliphatic index, stability profiling, antigenicity, allergenicity, and hydropathy of the ensemble, showed that the vaccine is highly stable, antigenic, and non-allergenic and produces multiple interactions with immune receptors upon docking. In addition, molecular dynamics simulation confirmed the stable binding and good dynamic properties of the vaccine–TLR complex. Furthermore, in silico and immune simulation of the developed MEVC for Y. pestis showed that the vaccine triggered strong immune response after several doses at different intervals. Neutralization of the antigen was observed at the third day of injection. Conclusively, the vaccine designed here for Y. pestis produces an immune response; however, further immunological testing is needed to unveil its real efficacy. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) causes chronic and acute hepatitis infections. As there is extreme variability in the HCV genome, no approved HCV vaccine has been available so far. An effective polypeptide vaccine based on the functionally conserved epitopes will be greatly helpful in curing disease. For this purpose, an immuno-informatics study is performed based on the published HCV subtype-3a from Pakistan. First, the virus genome was translated to a polyprotein followed by a subsequent prediction of T-cell epitopes. Non-allergenic, IFN-γ producer, and antigenic epitopes were shortlisted, including 5 HTL epitopes and 4 CTL, which were linked to the final vaccine by GPGPG and AAY linkers, respectively. Beta defensin was included as an adjuvant through the EAAAK linker to improve the immunogenicity of the polypeptide. To ensure its safety and immunogenicity profile, antigenicity, allergenicity, and various physiochemical attributes of the polypeptide were evaluated. Molecular docking was conducted between TLR4 and vaccine to evaluate the binding affinity and molecular interactions. For stability assessment and binding of the vaccine-TLR4 docked complex, molecular dynamics (MD) simulation and MMGBSA binding free-energy analyses were conducted. Finally, the candidate vaccine was cloned in silico to ensure its effectiveness. The current vaccine requires future experimental confirmation to validate its effectiveness. The vaccine construct produced might be useful in providing immune protection against HCV-related infections. [ABSTRACT FROM AUTHOR]

The 3-deoxy- d -manno-octulosonate 8-phosphate phosphatase (KdsC) catalyzes the hydrolysis of 3-deoxy- d -manno-octulosonate 8-phosphate (KDO 8-P) to 3-deoxy- d -manno-octulosonate (KDO) and inorganic phosphate in KDO biosynthesis pathway of Gram-negative bacteria lipopolysaccharide (LPS) hydrophobic lipid-A core. The essentiality of KDO for bacterial cell viability presents the possibility of its targeting to develop broad-spectrum antibacterial agents. In this study, a receptor based virtually screening method was put forward to identify novel lead inhibitory molecules for KdsC enzyme. Dynamics evaluation in solution revealed three complexes: Asinex-1197, Asinex-1705, and Asinex-1710 from Asinex antibacterial library as highly stable, involving conformational transition from open to close upon lead molecules binding and eloquent role of active pocket magnesium towards inhibitors binding and movements. Interconversion of local secondary structure elements in sequence region of Asp192-Asp208 covering motif β-turn, β-hairpin, and β-sheets is seen recurrently that could be in all likelihood of the pressure excreted on this region during closing conformation event or magnesium driven inhibitor adjustments. The binding free energy estimation predicted gas phase energy for all the three complexes dominating with major contribution from van der Waals energy (in case of Asinex-1705 and Asinex-1710) and balanced contributions of both electrostatic and van der Waals (in case of Asinex-1197). Key residues-scanning shortlisted Leu45, Asp185, Gy188, Arg231, and Lys255 as vital in the interaction network of magnesium and inhibitors at the binding site. Their crucial roles in net binding energy were reaffirmed via in silico site directed alanine scanning method. The filtered hits might be useful to further scaffolds addition and structural optimization to yield high affinity binders of KdsC enzyme, whose inhibition, in turn, will disrupt the outer membrane synthesis. Image 1 • Asinex-1197, Asinex-1705, and Asinex-1710 from Asinex antibacterial library are good binder to KdsC enzyme. • Close conformation of KdsC enzyme and the role of magnesium in lead molecules binding. • Leu45, Asp185, Gy188, Arg231, and Lys255 along with others of KdsC enzyme are vital in the compounds binding. [ABSTRACT FROM AUTHOR]

• Noval sulfaquinoxaline-derived SBs were synthesized and thoroughly characterized. • The synthesized SBs were assessed for different biological activities. • Among SBs, 6e exhibited superior antibacterial and anti-inflammatory properties. • Computational studies, including MD simulations, confirmed strong binding for SBs. • ADMET tests indicated excellent pharmacokinetic profiles for the synthesized SBs. Here, six sulfaquinoxaline Schiff bases were synthesized, and various analytical techniques such as FTIR, 1HNMR, and 13CNMR were employed for the characterization. Additionally, in-vitro biological studies were performed, including antibacterial, antifungal, antioxidant, antidiabetic, and anti-inflammatory activities. Computational tools such as molecular docking, DFT, and MD simulations were applied to explore the binding interactions, molecular structure, and chemical reactivity of sulfaquinoxaline SBs. Lastly, in-silico ADMET studies were performed to investigate drug-likeness properties, toxicity, and metabolism of the synthesized SBs. The prepared SBs demonstrated strong antibacterial activity against S. agalactiae and E. coli better than the standard drug, sulfaquinoxaline. The SBs possessed non-significant antioxidant (DPPH assay) and antidiabetic activities (α -amylase and α -glucosidase). All the derivatives depicted moderate anti-inflammatory activity except 6e (IC 50 131.95 µ g/mL) which presented comparable activity to the standard drug, diclofenac sodium (IC 50 127.27 µ g/mL). Computational analyses supported the experimental results, especially for compounds 5e and 6e confirming the robust binding affinities and enduring interactions of SBs with the protein target. In-silico drug-likeness analysis and ADMET prediction demonstrated that SBs were drug-like and had a satisfactory ADMET profile. [Display omitted] [ABSTRACT FROM AUTHOR]

• New methyl α-D-glucopyranoside (α-MGP) esters were designed and synthesized. Chemical structures and purity of these new (α-MGP) esters were confirmed by usual spectroscopic techniques. • In vitro antimicrobial and anticancer activity was investigated. Incorporation of various aliphatic and aromatic groups in (α-MGP) structure significantly increased their biological activity. • PASS prediction analysis indicated that the compounds were less potent as anti-carcinogenic agents (0.24 < Pa < 0.50) than as antimicrobial agents. • Molecular docking analysis was performed on synthesized (α-MGP) esters against three pathogen proteins. • Molecular dynamics (MD) simulations and binding free energy calculations revealed strong binding of designed compounds with the target proteins. • In silico pharmacokinetics calculations predicted improved pharmacokinetic properties of all (α-MGP) esters. Carbohydrates are abundant naturally occurring biomolecules that play essential roles in a wide variety of biological processes. In this paper, we describe the synthesis of a series of methyl α-D-glucopyranoside (α-MGP) esters through regioselective acylation, by modification of the hydroxyl (-OH) group. Synthesized 6- O -acyl derivatives were further converted to 2,3,4-tri- O -acyl esters, in good yield. Structures of the newly designed α-MGP esters (termed compounds 1–8) were elucidated by spectroscopic, physicochemical, and elemental analyses. PASS (prediction of activity spectra for substances) and in vitro screening of compounds 1–8 against human and plant pathogenic microorganisms revealed substantial antibacterial and antifungal activities. Most of them showed >70% inhibition of fungal mycelial growth. In vitro effect of compound 7 against Ehrlich ascites carcinoma (EAC) cells, by MTT colorimetric assay, showed 23.97% of cell growth inhibition with an IC 50 value of 1101.34 µg/ml. Molecular docking and nonbonding interaction studies were performed for three pathogen proteins Escherichia coli lectin FimH, Bacillus subtilis Obg GTP-binding protein, and Aspergillus flavus urate oxidase to evaluate binding affinities and interactions of compounds 1–8 with receptor proteins. A 100-ns molecular dynamics (MD) simulation study revealed the stable conformation and binding patterns/energy in a stimulating environment. In silico pharmacokinetics prediction and drug-likeness analysis of the compounds revealed improved kinetic parameters and satisfaction of all drug-likeness rules in regard to biological activity. Structure-activity relationship (SAR) studies, in combination with in vitro and in silico findings, indicated that among various acyl chains, lauroyl (C-12) and myristoyl (C-14), combined with α-MGP, were most effective against the tested bacterial and fungal pathogens. In conclusion, the designed α-MGP esters displayed enhanced pharmaceutical activities, and strong potential for development as antimicrobial agents. [Display omitted] [ABSTRACT FROM AUTHOR]

Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging health concern due to its high mortality rate of 35%. At present, no vaccine is available to protect against MERS-CoV infections. Therefore, an in silico search for potential antigenic epitopes in the non-redundant proteome of MERS-CoV was performed herein. First, a subtractive proteome-based approach was employed to look for the surface exposed and host non-homologous proteins. Following, immunoinformatics analysis was performed to predict antigenic B and T cell epitopes that were used in the design of a multi-epitopes peptide. Molecular docking study was carried out to predict vaccine construct affinity of binding to Toll-like receptor 3 (TLR3) and understand its binding conformation to extract ideas about its processing by the host immune system. We identified membrane protein, envelope small membrane protein, non-structural protein ORF3, non-structural protein ORF5, and spike glycoprotein as potential candidates for subunit vaccine designing. The designed multi-epitope peptide then linked to β-defensin adjuvant is showing high antigenicity. Further, the sequence of the designed vaccine construct is optimized for maximum expression in the Escherichia coli expression system. A rich pattern of hydrogen and hydrophobic interactions of the construct was observed with the TLR3 allowing stable binding of the construct at the docked site as predicted by the molecular dynamics simulation and MM-PBSA binding energies. We expect that the panel of subunit vaccine candidates and the designed vaccine construct could be highly effective in immunizing populations from infections caused by MERS-CoV and could possible applied on the current pandemic COVID-19. • In silico peptide based multi-epitopes vaccine design for MERS-CoV. • Designed vaccine is composed of B, T cell epitopes and adjuvant. • Vaccine is antigenic, non-allergic and has favorable physicochemical properties. • Dynamically, the vaccine binding mode and interactions are stable to TLR3 receptor. • Vaccine revealed robust electrostatic energies in complex with TLR3. [ABSTRACT FROM AUTHOR]

[Display omitted] • New 2,4-dihydro-1H-1,2,4-triazole-3-selones and 3,3′-di(4H-1,2,4-triazolyl)diselenides derivatives were synthesized and confirmed by IR, MS, and NMR. • Bactericidal and fungicidal activities were performed. • Molecular docking and dynamics simulations were carried out. The reaction of aromatic ring-substituted isoselenocyanates with 2-thiopheacetic and 4-pyridinecarboxylic acid hydrazides yielded selenosemicarbazides which were further converted into previously unknown 1,2,4-triazole-3-selones and 3,3′-di(4H-1, 2,4-triazolyl)diselenides. The structures of the obtained compounds were studied by NMR spectroscopy, IR spectroscopy, and high-resolution mass spectroscopy (HR-MS). The bactericidal and fungicidal activity of some obtained compounds was evaluated in molecular modeling studies such as docking and simulation studies. The compound 3ba was reported as the most promising compound to show robust binding energy with different antibacterial and antifungal compounds. The compounds were observed in strong hydrophilic and hydrophobic interactions and remained in stable binding conformation with the receptor enzymes. Furthermore, the interatomic interaction energies were dominated by Van der Waals and electrostatic energies indicating the formation of stable complexes. [ABSTRACT FROM AUTHOR]

• New hydrazide derivative was synthesized and characterized by X-ray diffraction. • The contributions for the crystal packing were determined with Hirshfeld surface. • Molecular properties, NBO, FMO analysis were theoretically investigated using DFT method. • In-silico assays were performed regarding the new hydrazide ligand towards COVID-19 proteins. • This study provided a useful reference for the design, development, and screening of novel drug discovery. In the fall of 2019, a new type of coronavirus took place in Wuhan city, China, and rapidly spread across the world and urges the scientific community to develop antiviral therapeutic agents. In our effort we have synthesized a new hydrazide derivative, (E)- N' -(1-(4-bromophenyl)ethylidene)-2-(6-methoxynaphthalen-2-yl)propanehydrazide for this purpose because of its potential inhibitory proprieties. The asymmetric unit of the title molecule consists of two independent molecules differing noticeably in conformation. In the crystal, the independent molecules are linked by N—H···O and C—H···O hydrogen bonds and C—H···π(ring) interactions into helical chains extending along the b-axis direction. The chains are further joined by additional C—H···π(ring) interactions into the full 3-D structure. To obtain a structure-activity relationship, the DFT-NBO analysis is performed to study the intrinsic electronic properties of the title compound. Molecular modeling studies were also conducted to examine the binding affinity of the compound for the SARS-CoV-2 main protease enzyme and to determine intermolecular binding interactions. The compound revealed a stable binding mode at the enzyme active pocket with a binding energy value of -8.1 kcal/mol. Further, stable dynamics were revealed for the enzyme-compound complex and reported highly favorable binding energies. The net MMGBSA binding energy of the complex is -37.41 kcal/mol while the net MMPBSA binding energy is -40.5 kcal/mol. Overall, the compound disclosed the strongest bond of ing the main protease enzyme and might be a good lead for further structural optimization. [ABSTRACT FROM AUTHOR]

[Display omitted] • By virtual screening three hit molecules were identified against the cathepsin D enzyme. • The compounds unveiled stable conformation with the enzyme. • It was found that the molecules have binding affinity of <−10 kcal/mol. • The systems root mean square deviation (RMSD) in simulated time is <3 Å. The cathepsin D is a pepsin-family aspartic protease enzyme that is ubiquitous and is known for its vital role in tumor progression and metastasis. This study considered its therapeutic potential and aimed to employ a comprehensive computational approach to identify and understand possible inhibition mechanisms of drug molecules from the asinex database, comprehensive marine natural products database, and medicinal plant databases. By virtual screening of the said databases, three-hit molecules: hit-1 (2-(1-(4-fluoro-3-methylbenzoyl)pyrrolidin-3-yl)-4-hydroxy-6-(2-hydroxypyridin-1-ium-3-yl)pyrimidine-1,3-diium), hit-2 (4-(3-(3-(4-fluorophenyl)-1,7-dihydroimidazo[1,2-a]pyrimidin-8-ium-5-yl)-1H-pyrrol-1-yl)-2-methylpyrimidine-1,3-diium), and hit-3 (5-(1-(2-cyclopentylacetyl)pyrrolidin-2-yl)-3-(4-fluorophenyl)-1,7-dihydroimidazo[1,2-a]pyrimidin-8-ium) were identified against the cathepsin D enzyme. The compounds unveiled stable conformational dynamics and formed several key short-distance hydrophilic and hydrophobic interactions. It was found that hit-1, hit-2, and hit-3 molecules have a binding affinity of <−10 kcal/mol for the cathepsin D enzyme. Molecular dynamics simulation analysis examined the systems as significantly stable in terms of binding mode and chemical interactions. The system's root mean square deviation (RMSD) in simulated time is <3 Å, which validates the docking and simulation data, binding free energies analysis including MM-GBSA, MM-PBSA, and WaterSwap analysis. The MM-GBSA analysis estimated −73.86, −75.8, and −87.02 net binding energies, while the MM-PBSA analysis estimated −70.58, −78.15, and −82.35 net free binding energies for Hit 1, Hit 2, and Hit 3, respectively. The binding interaction pointed towards stable interactions energy of compounds with cathepsin D, while the WaterSWAP analysis for the Hit-1 system, the Bennetts, FEP, and TI energy value is −36 kcal/mol, −37 kcal/mol, and −36 kcal/mol, respectively. The Hit-2 system has a binding energy of −39 kcal/mol (Bennetts), −39 kcal/mol (FEP), and −38 kcal/mol (TI). The Hit-3 complex was revealed to be more stable even than the control. The binding energy value of Bennetts, FEP, and TI is −42 kcal/mol, −41 kcal/mol, and −42 kcal/mol, respectively. Several hotspot residues were also highlighted in intermolecular interactions, and those, when mutated, impacted the overall binding energy of complexes. Lastly, the compounds were revealed to show favorable ADMET properties and thus could be regarded as promising leads for future experimental validation. [ABSTRACT FROM AUTHOR]

[Display omitted] • An effective biological property is observed for the compound. • A high stabilization energy from metal to ligand confirmed the NLO activity for Zn-metal complex. • The enzyme revealed several key active site residues to form short distance hydrophilic and hydrophobic contacts with the compound. The present work undertakes the study of novel thiocyanic complex, which have been obtained due to the interaction of cationic entities with the thiocyanate ligands. In fact, these latter are added to a transition metal leading to the production of novel solid-state complex that was studied and characterized by single crystal X-ray crystallography. However, (C 11 H 18 N 2 O)[Zn(SCN) 4 ] crystallizes in orthorhombic system with the non-centrosymmetric space group P 2 1 2 1 2 1 , with the following lattice parameters: a = 8.4726(2) Å, b = 14.6043 (7) Å, c = 17.1927 (14) Å with V = 2127.3 (14) Å3 and Z = 4. Infrared spectrum was registered to revel the vibrational modes of the compound, add to the study of the optical properties using a polar solvent to carry out the UV–visible analysis. Thermogravimetric analysis techniques (TGA) and thermo-differential analysis techniques (DTA) were carried out to account for the thermal decomposition of complex. Furthermore, the antibacterial properties were determined against some bacteria. In order to gain insights into the role of weak molecular interactions in the complex that influence the self-assembly process and crystal packing, Hirshfeld surface analysis and DFT calculation were also performed. Furthermore, molecular docking and molecular dynamic simulations were performed for the compound against different antibacterial targets to identify to which target the compound show the best binding affinity. The MurF enzyme, which catalyzed the last cytoplasmic step of bacterial peptidoglycan synthesis, among the target was revealed to show better interactions with the enzyme and formed strong and stable intermolecular complex. [ABSTRACT FROM AUTHOR]

New complex compounds (I) - (IV) were synthesized by the reaction of 1-(2-fluorofluorophenyl) -1,4-dihydro-5 H -tetrazole-5-thione (HL 1 ), 1-(2-methylphenyl)-1,4-dihydro-5 H -tetrazole-5-thione (HL 2 ) and 1-(2-chlorochlorophenyl)-1,4-dihydro-5 H -tetrazole-5-thione (HL 3 ) with cadmium chloride. By X-ray diffraction analysis, molecular and crystal structures of complexes (I), (II), (III) and (I V) are determined. (CIF files CCDC № 2,003,797 (I), 1,993,454 (II), 2,151,359 (III), 2,098,997 (IV)). Hirshfeld surface analysis, frontier orbital analysis, atomic charges, electrostatic potential, nonlinear optical properties, and natural bond analysis of all three‑cadmium metal-organic complexes were discussed. A molecular docking study was used to investigate compounds' binding and interactions with DNA molecules, which predicted compound I as the best binder at the DNA minor groove and demonstrated closed distance interactions. In a long run of molecular dynamics simulations, the compound I complex was also depicted with good dynamics. [Display omitted] • Characterizing all new synthesizes complexes by all possible techniques to establish their chemical formulae. • Complexes (I), (II) and (IV) were determined by X-ray diffraction analysis. • Hirshfeld surface analysis revealed the fingerprint plots and molecular surface contours. • Theoretical study via DFT approach, B3LYP method. • Molecular docking and molecular dynamics simulations of the complexes have been performed. [ABSTRACT FROM AUTHOR]

This current research work is focused on the synthesis of sulfonyl-mediated hydrazones, its exploration as anticholinesterase inhibitors, in vitro biological evaluation, and computational studies. A series of 21 novel bis(acylhydrazones) (4a-u) have been synthesized in good to excellent yields using 4,4ꞌ-sulfonyldiphenol as the precursor. Characterization of the synthesized compounds was achieved via spectroscopic techniques i.e. UV, FT-IR, NMR (1H and 13C), and HRMS. In vitro anticholinesterase activity of these compounds was performed using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) as cholinesterase enzymes. Among all the compounds tested, compounds 4 g and 4 h were found to be the most significant AChE inhibitions with IC 50 values of 101.4 and 102.7 µM as compared to the standard cholinesterase inhibitor i.e., galantamine (IC 50 = 104.5 µM). Additionally, compound 4 g was also found to be an excellent inhibitor of BChE with an IC 50 value of 136.0 µM as compared to the standard galantamine (IC 50 = 156.8 µM). Molecular docking of the most active compounds 4 g and 4 h also supported their potential to interact with cholinesterase enzymes. Further affirmation on the intermolecular stability of the docked complexes was achieved by molecular dynamics simulation for 100 ns with mean deviations ∼2 Å. Residue level fluctuations analysis also interpreted the good stability of compounds interacting pocket residues. Lastly, binding free energy analysis was performed that decipher the intermolecular interactions that are dominated by both van der Waals and electrostatic energies. In short, both theoretical and experimental studies unveiled the compounds as potent blockers of cholinesterase enzymes. • A series of 21 novel bis(acylhydrazones) (4a-u) have been synthesized. • Compounds 4 g and 4 h revealed significant AChE inhibitions. • Compound 4 g was also found to be an excellent inhibitor of BChE. • Molecular docking of 4 g and 4 h supported their potential to interact with enzymes. • Binding free energy analysis deciphers domination of van der Waals and electrostatic energies. [Display omitted] [ABSTRACT FROM AUTHOR]

• The 3,3′-Ethane-1,2-diylbis(2-benzylidene-1,3-thiazolidin-4-one was characterized by X-ray structural analysis. • DFT calculations and HOMO-LUMO frontier molecular orbitals analysis for the compound were performed. • Hirshfeld surface analysis, interaction energies, and energy frameworks were discussed. • Molecular docking, followed by molecular dynamics simulation and MM-GBSA binding free energy was carried out to predict the binding affinity of 4 for α-amylase enzyme. A new thiazolidine derivative, 3,3′-ethane-1,2-diylbis(2-benzylidene-1,3-thiazolidin-4-one (4) was synthesized and the product obtained was characterized by NMR, IR and mass spectral studies, and the structure was confirmed by single crystal X-ray diffraction studies. The title compound crystallizes in the monoclinic space group P 2 1 / n, the unit cell parameters are a = 15.9505(8) Å, b = 6.6818(3) Å, c = 18.1799(9) Å, β = 94.249(2)° and Z = 4 at 150 K. In the title molecule, C 20 H 18 N 4 O 2 S 2 , the thiazolidine rings adopt a "pincer" conformation with the phenylimino substituents extending outwards on both sides. A layer structure is formed in the crystal by C—H···N and C—H···O hydrogen bonds. A Hirshfeld surface analysis was used to explore the nature of the intermolecular interactions in the crystal structure employing molecular surface contours and 2D fingerprint plots have been used to examine molecular shapes. The frontier orbital analysis shows that 4 should be more sensitive to a nucleophilic attack than an electrophilic attack. Molecular docking, followed by molecular dynamics simulation and MM-GBSA binding free energy was carried out to predict the binding affinity of 4 for α-amylase enzyme. These analyses revealed good intermolecular stability of the complex with stable high affinity intermolecular complex formation of high equilibrium nature. [Display omitted] [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS) that remains incurable. Withametelin (WMT), a phytosterol, showed diverse biological activities isolated from the leaves of Datura innoxa. In the present study, we used an in vitro model of HT22 and BV - 2 cell lines and an in vivo murine model of MS, experimental autoimmune encephalomyelitis (EAE), to explore the antioxidant and anti neuroinflammatory potential of WMT. The results showed that pretreatment with WMT markedly inhibited H 2 O 2 - induced cytotoxicity and oxidative stress in a dose-dependent manner. Correspondingly, WMT post-immunization treatment significantly attenuated EAE-induced clinical score, weight loss, neuropathic pain behaviors, and motor dysfunction. It markedly lowers EAE-induced elevated circulating leucocytes, spinal deformity, and splenomegaly. It strikingly inhibited the Evans blue and FITC extravasation in the brain. It remarkably reversed the EAE-induced histopathological alteration of the brain, spinal cord, eye, and optic nerve. It significantly intensified the antioxidant defense mechanism by improving the expression level of nuclear factor-erythroid-related factor-2 (Nrf2), heme-oxygenase-1 (HO-1) but reducing the expression level of the Kelch-like-ECH-associated-protein-1 (keap-1), inducible-nitric-oxide-synthase (iNOS) in the CNS. Likewise, it markedly suppressed neuroinflammation by reducing the expression level of toll-like-receptor 4 (TLR4), nuclear-factor-kappa-B (NF-κB), activator-protein-1 (AP-1) but increased the expression level IkB-α in the CNS. Furthermore, molecular dynamics simulations and MMPBSA binding free energies were determined to validate the dynamic stability of complexes and shed light on the atomic level intermolecular interaction energies. Taken together, this study showed that WMT has significant neuroprotective potential in EAE via modulation of Nrf2 mediated-oxidative stress and NF-κB mediated inflammation. [Display omitted] • Withametelin ameliorated EAE-associated clinical symptoms. • Withametelin reversed EAE-associated histopathological alteration in the CNS. • Withametelin suppressed the BBB permeability, oxidative stress & neuroinflammation. • Withametelin inhibited the apoptosis, protein, and myelin damage in the EAE mice. • Withametelin modulates the expression of TLR4/IκB-α/NF-κB/AP-1 & Nrf2/Keap-1/HO-1/iNOS/Bcl-2. [ABSTRACT FROM AUTHOR]

• A newly benzimidazole derivative has been synthesized and characterized. • Its structural is confirmed by XRD and compatible with DFT findings. • The compound exhibited promising NLO properties. • Molecular docking and molecular dynamics studies were performed for the compound. The present article describes the synthesis of the new compound 2-methylbenzimidazo[1,2- a pyrimidin-4(1 H)-one. The electronic and spatial structure of this molecule was studied theoretically and experimentally. The title molecule, C 11 H 9 N 3 O, is slightly twisted and bowed based on the recent crystallographic study, while the DFT-B3LYP study shows that the title compound is fully planar in the gas phase. This discrepancy between the experimentally determined geometry and the B3LYP optimized one may be due to the crystal packing. In the crystal, a layer structure is formed by N—H•••N and C—H•••O hydrogen bonds together with π-stacking and C—H•••π(ring) interactions. However, the Hirshfled surface analysis showed that the most important intermolecular interaction for the title compound is the H•••H contact. Based on the wide biological interest, molecular docking and molecular dynamics studies were performed for the above titled compound with the poly(ADP-ribose)polymerase (PARP) enzyme target and the result shows that there is a good binding affinity and stability in PARP complex system. [Display omitted] [ABSTRACT FROM AUTHOR]

• Buchwald Hartwig amination of thiazole were only possible with Pd-PEPPSI catalyst. • Compound 3f was found to be most active against tested bacteria. • 3f docking with FabH enzyme showed deep and chemically stable complex formation. • Molecular dynamics simulation affirms the docking studies. Bacterial FabH enzyme is a broad-spectrum antimicrobial target and can be used in the design of novel antibiotics. This study reports chemical synthesis of thiazole based amine compounds as FabH inhibitors, followed by biological evaluation, and computational drug designing analysis with ultimate objective to guide further biological optimization of the identified hits. The compounds were synthesized through Pd-PEPPSI catalyzed cross coupling strategy for the Buchwald-Hartwig amination of thiazole-substituted aryl bromide. Pd-PEPPSI pre-catalysts were utilized for the cross couple with the diverse range of functionalized electron-deficient and electron-rich anilines and aliphatic amines. The thiazole based heteroaryl bromide coupling was found to be challenging and only specialized Pd-PEPPSI-IPr and Pd-PEPPSI-IPent catalysts were found to be effective providing the coupling product yield in the range of 78% to 99%. Biological investigation depicted compound 3f to be effective against Bacillus subtilis , Staphylococcus aureus , Staphylococcus epidermis , and Escherichia coli with mean + standard deviation value of 9.6 ± 0.4, 11.6 ± 0.4, 15.6 ± 0.4, and 11.6 ± 0.4, respectively. This compound is also active against free radicals with EC 90 value of 39.45 µg/ml. Comparative docking predictions unravel the 3f binding mode at FabH active tunnel as such to block complete access for the natural substrate and involved balanced hydrogen and hydrophobic interactions. FabH- 3f complex dynamics in solution found the docked conformation between the protein and compound of higher stability with mean carbon alpha deviation of 1.87 Å and mean residual deviation of 0.88 Å. Intermolecular interactions analysis depicted Asn274 from FabH active pocket to be significant in compound holding and strengthening of interaction as the simulation progresses. This was supported further by radial distribution function (RDF) and axial frequency distribution (AFD) that demonstrated the high distribution of compound atoms in close proximity of Asn274 residue and decrease in interaction distance. Further, the docking and simulation findings were validated through MMPB/GBSA methods that complements the compound affinity for the said target. In a nutshell, the identified hit could be subjected to structure, biological and pharmacokinetic optimization for development of effective FabH inhibitors. [ABSTRACT FROM AUTHOR]