Molecular Docking Interaction Research Articles

Multidrug Antimicrobial Resistance and Molecular Detection of mcr-1 Gene in Salmonella Species Isolated from Chicken.

Simple SummaryColistin is a widely used antibiotic against infections caused by extensively drug-resistant Gram-negative bacteria. It is critical to track and monitor the presence of mcr-like genes and colistin resistance to protect a last resort treatment against highly antibiotic-resistant bacteria. In the present study, the colistin resistance gene mcr-1 was investigated, and its in-silico functional analysis in Salmonella isolates was determined. Out of 100 chicken samples (liver and intestine), 82 Salmonella spp. were isolated and characterized. Antimicrobial sensitivity was determined using different antimicrobial agents. The isolates were characterized using PCR targeting genus-specific invA and mcr-1 genes followed by in-silico functional analysis. The majority of isolates (92.68%) was found highly resistant to colistin, which demonstrated the occurrence of the colistin resistance mcr-1 gene in Salmonella isolates of chicken origin in Bangladesh. The study also showed the in-silico functional analysis and phylogenetic relationship of the colistin resistance mcr-1 gene among Salmonella isolates. The findings of the present study highlight the increasing issue of transferable colistin resistance and call for immediate action and measures to review the imprudent use of colistin in poultry production systems in Bangladesh.Colistin (polymyxin E) is widely used in animal and human medicine and is increasingly used as one of the last-resort antibiotics against Gram-negative bacilli. Due to the increased use of colistin in treating infections caused by multidrug-resistant Gram-negative bacteria, resistance to this antibiotic ought to be monitored. The study was undertaken to elucidate the molecular mechanisms, genetic relationships and phenotype correlations of colistin-resistant isolates. Here, we report the detection of the mcr-1 gene in chicken-associated Salmonella isolates in Bangladesh and its in-silico functional analysis. Out of 100 samples, 82 Salmonella spp. were isolated from chicken specimens (liver, intestine). Phenotypic disc diffusion and minimum inhibitory concentration (MIC) assay using different antimicrobial agents were performed. Salmonella isolates were characterized using PCR methods targeting genus-specific invA and mcr-1 genes with validation for the functional analysis. The majority of the tested Salmonella isolates were found resistant to colistin (92.68%), ciprofloxacin (73.17%), tigecycline (62.20%) and trimethoprim/sulfamethoxazole (60.98%). When screened using PCR, five out of ten Salmonella isolates were found to carry the mcr-1 gene. One isolate was confirmed for Salmonella enterica subsp. enterica serovar Enteritidis, and other four isolates were confirmed for Salmonella enterica subsp. enterica serovar Typhimurium. Sequencing and phylogenetic analysis revealed a divergent evolutionary relationship between the catalytic domain of Neisseria meningitidis lipooligosaccharide phosphoethanolamine transferase A (LptA) and MCR proteins, rendering them resistant to colistin. Three-dimensional homology structural analysis of MCR-1 proteins and molecular docking interactions suggested that MCR-1 and LptA share a similar substrate binding cavity, which could be validated for the functional analysis. The comprehensive molecular and in-silico analyses of the colistin resistance mcr-1 gene of Salmonella spp. of chicken origin in the present study highlight the importance of continued monitoring and surveillance for antimicrobial resistance among pathogens in food chain animals.

Anticancer potential of rhizome extract and a labdane diterpenoid from Curcuma mutabilis plant endemic to Western Ghats of India

Zingiberaceae plants are well known for their use in ethnomedicine. Curcuma mutabilis Škorničk., M. Sabu & Prasanthk., is an endemic Zingiberaceae species from Western Ghats of Kerala, India. Here, we report for the first time, the anticancer potential of petroleum ether extract from C. mutabilis rhizome (CMRP) and a novel labdane diterpenoid, (E)-14, 15-epoxylabda-8(17), 12-dien-16-al (Cm epoxide) isolated from it. CMRP was found to be a mixture of potent bioactive compounds including Cm epoxide. Both the extract and the compound displayed superior antiproliferative activity against several human cancer cell lines, without any display of cytotoxicity towards normal human cells such as peripheral blood derived lymphocytes and erythrocytes. CMRP treatment resulted in phosphatidylserine externalization, increase in the levels of intracellular ROS, Ca2+, loss of mitochondrial membrane potential as well as fragmentation of genomic DNA. Analyses of transcript profiling and immunostained western blots of extract-treated cancer cells confirmed induction of apoptosis by both intrinsic and extrinsic pathways. The purified compound, Cm epoxide, was also found to induce apoptosis in many human cancer cell types tested. Both CMRP and the Cm epoxide were found to be pharmacologically safe in terms of acute toxicity assessment using Swiss albino mice model. Further, molecular docking interactions of Cm epoxide with selected proteins involved in cell survival and death were also indicative of its druggability. Overall, our findings reveal that the endemic C. mutabilis rhizome extract and the compound Cm epoxide isolated from it are potential candidates for development of future cancer chemotherapeutics.

Computational drug repurposing strategy predicted peptide-based drugs that can potentially inhibit the interaction of SARS-CoV-2 spike protein with its target (humanACE2).

Drug repurposing for COVID-19 has several potential benefits including shorter development time, reduced costs and regulatory support for faster time to market for treatment that can alleviate the current pandemic. The current study used molecular docking, molecular dynamics and protein-protein interaction simulations to predict drugs from the Drug Bank that can bind to the SARS-CoV-2 spike protein interacting surface on the human angiotensin-converting enzyme 2 (hACE2) receptor. The study predicted a number of peptide-based drugs, including Sar9 Met (O2)11-Substance P and BV2, that might bind sufficiently to the hACE2 receptor to modulate the protein-protein interaction required for infection by the SARS-CoV-2 virus. Such drugs could be validated in vitro or in vivo as potential inhibitors of the interaction of SARS-CoV-2 spike protein with the human angiotensin-converting enzyme 2 (hACE2) in the airway. Exploration of the proposed and current pharmacological indications of the peptide drugs predicted as potential inhibitors of the interaction between the spike protein and hACE2 receptor revealed that some of the predicted peptide drugs have been investigated for the treatment of acute respiratory distress syndrome (ARDS), viral infection, inflammation and angioedema, and to stimulate the immune system, and potentiate antiviral agents against influenza virus. Furthermore, these predicted drug hits may be used as a basis to design new peptide or peptidomimetic drugs with better affinity and specificity for the hACE2 receptor that may prevent interaction between SARS-CoV-2 spike protein and hACE2 that is prerequisite to the infection by the SARS-CoV-2 virus.

DockIT: a tool for interactive molecular docking and molecular complex construction.

DockIT is a tool that has a unique set of physical and graphical features for interactive molecular docking. It enables the user to bring a ligand and a receptor into a docking pose by controlling relative position and orientation, either with a mouse and keyboard, or with a haptic device. Atomic interactions are modelled using molecular dynamics-based force-fields with the force on the ligand being felt on a haptic device. Real-time calculation and display of intermolecular hydrogen bonds and multipoint collision detection either using maximum force or maximum atomic overlap, mean that together with the ability to monitor selected intermolecular atomic distances, the user can find physically feasible docking poses that satisfy distance constraints derived from experimental methods. With these features and the ability to output and reload docked structures it can be used to accurately build up large multi-component molecular systems in preparation for molecular dynamics simulation. DockIT is available free of charge for non-commercial use at http://www.haptimol.co.uk/downloads.htm. It requires a windows computer with GPU that supports OpenCL 1.2 and OpenGL 4.0. It may be used with a mouse and keyboard, or a haptic device from 3DSystems.

Characterization of α-Glucosidase Inhibitors from Psychotria malayana Jack Leaves Extract Using LC-MS-Based Multivariate Data Analysis and In-Silico Molecular Docking.

Psychotria malayana Jack has traditionally been used to treat diabetes. Despite its potential, the scientific proof in relation to this plant is still lacking. Thus, the present study aimed to investigate the α-glucosidase inhibitors in P. malayana leaf extracts using a metabolomics approach and to elucidate the ligand–protein interactions through in silico techniques. The plant leaves were extracted with methanol and water at five various ratios (100, 75, 50, 25 and 0% v/v; water–methanol). Each extract was tested for α-glucosidase inhibition, followed by analysis using liquid chromatography tandem to mass spectrometry. The data were further subjected to multivariate data analysis by means of an orthogonal partial least square in order to correlate the chemical profile and the bioactivity. The loading plots revealed that the m/z signals correspond to the activity of α-glucosidase inhibitors, which led to the identification of three putative bioactive compounds, namely 5′-hydroxymethyl-1′-(1, 2, 3, 9-tetrahydro-pyrrolo (2, 1-b) quinazolin-1-yl)-heptan-1′-one (1), α-terpinyl-β-glucoside (2), and machaeridiol-A (3). Molecular docking of the identified inhibitors was performed using Auto Dock Vina software against the crystal structure of Saccharomyces cerevisiae isomaltase (Protein Data Bank code: 3A4A). Four hydrogen bonds were detected in the docked complex, involving several residues, namely ASP352, ARG213, ARG442, GLU277, GLN279, HIE280, and GLU411. Compound 1, 2, and 3 showed binding affinity values of −8.3, −7.6, and −10.0 kcal/mol, respectively, which indicate the good binding ability of the compounds towards the enzyme when compared to that of quercetin, a known α-glucosidase inhibitor. The three identified compounds that showed potential binding affinity towards the enzymatic protein in molecular docking interactions could be the bioactive compounds associated with the traditional use of this plant.

Multiple epitope-based vaccine prediction against SARS-CoV-2 spike glycoprotein

The global emergence of novel coronavirus disease and its rapid global expansion over a short span of time require effective countermeasures to combat it. Development of a specific vaccine can induce an optimal antibody response, thus providing immunity against it. Our study proposes a detailed and comprehensive immunoinformatic approach that can be applied to the currently available coronavirus protein data in the online server for vaccine candidate development. We have identified the receptor binding domain (RBD) of structural spike protein (S1) as a potential target for immunity against COVID- 19 infection. Epitope prediction illustrated cytotoxic T-cell epitopes, helper T-cell epitopes, and B-cell epitopes associated with the target protein. These were joined through specific linkers along with adjuvant beta-defensin located at the N-terminal to create a multi epitope subunit vaccine (MESV). The specificity in the binding of the devised vaccine candidate to the TLR-3 immune cell receptor was evaluated via molecular docking interaction studies. Good docking score combined with robust interactions in the binding cavity certified the stringency of the engineered vaccine. Molecular dynamics simulation data showed minimal variation of the root-mean square deviations (RMSDs) and root-mean-square fluctuations (RMSFs) which confirmed the interaction stability. These results obtained from various in-silico experiments indicate the potency of this vaccine candidate as a probable therapeutic agent against COVID-19. Vaccination strategies targeting conserved epitope-based immune response would be beneficial in providing cross protection across beta-coronaviruses, and such vaccines would be resistant to the ever-evolving viruses. Communicated by Ramaswamy H. Sarma

Design and development of Tetrahydro-Quinoline derivatives as dual mTOR-C1/C2 inhibitors for the treatment of lung cancer

Lung cancer is one of the most prevailed cancer worldwide. Many genes get mutated in lung cancer but the involvement of EGFR, KRAS, PTEN and PIK3CA are more common. Unavailability of potent drugs and resistance to the available drugs are major concern in the treatment of lung cancer. In the present research, mTOR was selected as an important alternative target for the treatment of lung cancer which involves the PI3K/AKT/mTOR pathway. We studied binding interactions of AZD-2014 with the mTOR protein to identify important interactions required to design potent mTOR inhibitors which was supported by QSAR studies. Pharmacophore based virtual screening studies provided core scaffold, THQ. Based on molecular docking interactions, 31 THQ derivatives were synthesized and characterized. All compounds were screened for cellular mTOR enzyme assay along with antiproliferative activity against the panel of cancerous cell lines, from which 6 compounds were further screened for colony forming assay. Two most potent compounds, HB-UC-1 and HB-UC-5, were further screened for flow cytometry analysis, gene expression study and western blot analysis. Gene expression study revealed the efficiency of compound HB-UC-1 against both mTORC1 and mTORC2 by affecting downstream regulators of mTORC1 (E4BP4, eIF4EBP1) and mTORC2 (PCK1), respectively. In western blot analysis, both compounds, inhibited phosphorylation of AKT S473 which proved the efficiency these compounds against the mTORC2. These two compounds were further screened for in-vivo biological evaluation. Both compounds increased lifespan of cancer-bearing animals with improvement in mean survival time. Further, in bezopyrene induced lung cancer animal model, both compounds showed effectiveness through the biochemical parameters and histopathological evaluation of the lung tissue. In future, potent hit compound from this series could be modified to develop lead mTOR inhibitors for the treatment of lung cancer.

Synthesis of novel coumarin analogues: Investigation of molecular docking interaction of SARS-CoV-2 proteins with natural and synthetic coumarin analogues and their pharmacokinetics studies.

The severe acute respiratory syndrome coronavirus, identified as SARS-CoV-2, initially established in Wuhan, China at the end of 2019, affects respiratory infections known as COVID-19. In an extraordinary manner, COVID-19 is affecting human life and has transformed a global public health issue into a crisis. Natural products are already recognized owing to the massive advantageous window and efficient antioxidant, antiviral immunomodulatory, and anti-inflammatory belongings. Additionally, the object of the present study was to demonstrate the inhibitory potential of the natural products coumarins and its analogues alongside SARS coronavirus. The present work, focuses on the synthesis of new coumarin analogues and characterized by FT-IR, 1H and 13C NMR, elemental analyses, and mass spectra. The recently synthesised compounds were projected conceptual association for COVID-19 protease and also to explore in anticipation if this protein will help target protease inhibitor drugs such as Calanolide A, Cardatolide A, Collinin, Inophyllum A, Mesuol, Isomesuol, Pteryxin, Rutamarin, Seselin and Suksdorin. The natural coumarin analogues docking scores were compared to standard Hydroxychloroquine. While the 3D module of SARS coronavirus main protease was predicted with the SWISS MODEL web server, as well as biochemical interaction tests were performed with the AutoDock Vina tool between the target protein with ligands. This research further showed that all the protease inhibitors accessed the target protein with negative dock energy. Molecular docking studies found that the natural coumarin analogue Inophyllum A showed an exceptional potential for inhibition with a binding energy of −8.4 kcal/mol. The synthetic coumarin analogues 1m and 1p both demonstrated a similar binding energy, inhibition potential of −7.9 kcal / mol as opposed to hydroxychloroquine and co-crystallized ligand alpha-ketoamide with binding energy values of −5.8 and −6.6 kcal / mol. All compounds evaluated were known as drug-like in nature, passing Lipinski's “Law of 5” with 0 violations except for alpha-ketoamide, passing Lipinski's “Rule of 5” with 1 violation (MW > 500). The inhibitor binding in silico research thus offers a structural understanding of COVID-19 and molecular interactions across the known protease inhibitors centred on the findings of the multiple sequence alliance.

A multi-stage virtual screening of FDA-approved drugs reveals potential inhibitors of SARS-CoV-2 main protease

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing global health emergency. Repurposing of approved pharmaceutical drugs for COVID-19 treatment represents an attractive approach to quickly identify promising drug candidates. SARS-CoV-2 main protease (Mpro) is responsible for the maturation of viral functional proteins making it a key antiviral target. Based on the recently revealed crystal structures of SARS-CoV-2 Mpro, we herein describe a multi-stage virtual screening protocol including pharmacophore screening, molecular docking and protein-ligand interaction fingerprints (PLIF) post-docking filtration for efficient enrichment of potent SARS-CoV-2 Mpro inhibitors. Potential hits, along with a cocrystallized control were further studied via molecular dynamics. A 150-ns production trajectory was followed by RMSD, free energy calculation, and H-bond analysis for each compound. The applied virtual screening protocol led to identification of five FDA-approved drugs with promising binding modes to key subsites of the substrate-binding pocket of SARS-CoV-2 Mpro. The identified compounds belong to different pharmaceutical classes, including several protease inhibitors, antineoplastic agents and a natural flavonoid. The drug candidates discovered in this study present a potential extension of the recently reported SARS-CoV-2 Mpro inhibitors that have been identified using other virtual screening protocols and may be repurposed for COVID-19 treatment.

Synthesis and Biological Evaluation of Alanine Derived Bioactive p-Toluenesulphonamide Analogs

Sulphonamides and carboxamides have great pharmacological importance. The purpose of the study was to synthesize alanine-derived bioactive sulphonamides bearing carboxamides and evaluate their biological activities. The reaction of p-toluenesulphonyl chloride with L-alanine afforded compound 1, which was acetylated to obtain compound 2. The chlorination and ammonolysis of compound 2 gave the carboxamide backbone (3) which was coupled with aryl/heteroaryl halides to afford the hybrid compounds 4, 5 and 6. Structures were confirmed by FTIR, 1H-NMR, 13C-NMR spectra and elemental analytical data. The in vitro antimicrobial properties were determined by agar dilution, and the antioxidant properties were also investigated. Molecular docking interactions of the analogues were determined using PyRx. Compounds 4, 5 and 6 exhibited excellent in vitro antimicrobial properties in the range of 0.5-1.0mg/ml while compounds 1and 2 had half-maximal inhibitory concentration (IC50) of 1.11±0.15µg/ml and 1.12±0.13µg/ml respectively. For the molecular docking studies, compounds 5 and 6 displayed the best antitrypanosomal activity with binding affinities of -13.95 and -13.51kcal/mol respectively while compound 4 showed the highest in silico antimalarial activity having binding affinity of -11.95kcal/mol. All the alanine derived sulphonamides were observed to be potential antimicrobial, antioxidant, antitrypanosomal and antimalarial agents following the biological activities studies.

Molecular Docking Unmasks Potent Phytoligands against SARS CoV 2 Spike Glycoprotein, Main Protease, Papain like Protease and RNA dependent RNA Polymerase

The recent coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has offered a unique challenge for human survival. However, there is no available known prophylaxis, therapeutic intervention, and vaccine candidate against SARS-CoV-2 to date. We aimed towards identifying novel phytoligands from widely available botanical resources which could serve as potential inhibitors against SARS-CoV-2. Based on literature review, database search, ADMET, and drug-likeness, 55 phytoligands and 8 synthetic repurposing drugs were screened and tested against SARS-CoV-2 spike glycoprotein, main protease, papain-like protease, and RNA-dependent RNA polymerase using molecular docking and protein-ligand interaction. All phytoligands and repurposing drugs showed binding affinity based inhibitory potential against the viral proteins. The highest binding affinities of phytoligands towards antiviral targets were exhibited by colchicine and oleic acid, and that of repurposing drugs was shown by saquinavir and nelfinavir. Capsaicin, oleic acid, azithromycin, nelfinavir, remdesivir, and saquinavir were acted as plausible broad-spectrum inhibitors. Hydrogen bonds and hydrophobic interactions of amino acids were varied significantly within the conserved domain along with glutamic acid richness. Further investigation should be carried out to obtain the synergistic effect using cell-based assays, animal models, and clinical trials to discover novel phytomedicine against SARS-CoV-2.

Synthesis, Molecular Docking, and In Vitro Boron Neutron Capture Therapy Assay of Carboranyl Sinomenine.

In comparison with pristine sinomenine and carborane precursors, the calculations of molecular docking with matrix metalloproteinases (MMPs) and methylcarboranyl-n-butyl sinomenine showed improved interactions. Accordingly, methylcarboranyl-n-butyl sinomenine shows a high potential in the treatment of rheumatoid arthritis (RA) in the presence of slow neutrons. The reaction of potassium salt of sinomenie, which is generated from the deprotonation of sinomenine (1) using potassium carbonate in a solvent of N,N-dimethyl formamide, with 4-methylcarboranyl-n-butyl iodide, (2) forms methylcarboranyl-n-butyl sinomenine (3) in 54.3% yield as a new product. This new compound was characterized by 1H, 13C, and 11B NMR spectroscopy, FT-IR spectroscopy, and elemental analyses to confirm its molecular composition. In addition to molecular docking interactions with MMPs, the in vitro killing effects of 3, along with its toxicity measurements, exhibited its potential to be the new drug delivery agent for boron neutron capture synovectomy (BNCS) and boron neutron capture therapy (BNCT) for the treatment of rheumatoid arthritis (RA) and cancers in the presence of slow neutrons, respectively.

Predicting the Molecular Mechanism of EGFR Domain II Dimer Binding Interface by Machine Learning to Identify Potent Small Molecule Inhibitor for Treatment of Cancer.

Epidermal growth factor receptor (EGFR) is a transmembrane druggable target controlling cellular differentiation, proliferation, migration, survival and invasion. EGFR activation mainly occurs by its homo/hetro dimerization molecular phenomenon leading to tumor development and invasion. Several tyrosine kinase based inhibitors were discovered as potent anti-cancer drugs. However, mutations in its kinase domain confer resistance to most of these drugs. To overcome this drug resistance, development of small molecule inhibitors disrupting the EGFR Domain II dimer binding by machine learning methods are promising. Based on this insight, a structure-based drug repurposing strategy was adopted to repurpose the existing FDA approved drugs in blocking the EGFR Domain II mediated dimerization. We identified five best repurposed drug molecules showing good binding affinity at its key arm-cavity dimer interface residues by different machine learning methods. The molecular mechanisms of action of these repurposed drugs were computationally validated by molecular electrostatics potential mapping, point mutations at the dimer arm-cavity binding interface, molecular docking and receptor interaction studies. The present machine learning strategy thus forms the basis of identifying potent and putative small molecule drugs for the treatment of different types of cancer.

GC\u2013MS analysis of phytoconstituents from Amomum nilgiricum and molecular docking interactions of bioactive serverogenin acetate with target proteins

Amomum nilgiricum is one of the plant species reported from Western Ghats of India, belonging to the family Zingiberaceae, with ethno-botanical values, and is well-known for their ethno medicinal applications. In the present investigation, ethyl acetate and methanol extracts of A. nilgiricum were analyzed by Fourier transform infrared spectrometer (FTIR) and gas chromatography-mass spectrometry (GC–MS) to identify the important functional groups and phytochemical constituents. The FTIR spectra revealed the occurrence of functional characteristic peaks of aromatic amines, carboxylic acids, ketones, phenols and alkyl halides group from leaf and rhizome extracts. The GC–MS analysis of ethyl acetate and methanol extracts from leaves, and methanol extract from rhizomes of A. nilgiricum detected the presence of 25 phytochemical compounds. Further, the leaf and rhizome extracts of A. nilgiricum showed remarkable antibacterial and antifungal activities at 100 mg/mL. The results of DPPH and ferric reducing antioxidant power assay recorded maximum antioxidant activity in A. nilgiricum methanolic leaf extract. While, ethyl acetate leaf extract exhibited maximum α-amylase inhibition activity, followed by methanolic leaf extract exhibiting aldose reductase inhibition. Subsequently, these 25 identified compounds were analyzed for their bioactivity through in silico molecular docking studies. Results revealed that among the phytochemical compounds identified, serverogenin acetate might have maximum antibacterial, antifungal, antiviral, antioxidant and antidiabetic properties followed by 2,4-dimethyl-1,3-dioxane and (1,3-13C2)propanedioic acid. To our best knowledge, this is the first description on the phytochemical constituents of the leaves and rhizomes of A. nilgiricum, which show pharmacological significance, as there has been no literature available yet on GC–MS and phytochemical studies of this plant species. The in silico molecular docking of serverogenin acetate was also performed to confirm its broad spectrum activities based on the binding interactions with the antibacterial, antifungal, antiviral, antioxidant and antidiabetic target proteins. The results of the present study will create a way for the invention of herbal medicines for several ailments by using A. nilgiricum plants, which may lead to the development of novel drugs.

Synthesis, Molecular Docking and Pharmacological Investigation of Some 4-Methylphenylsulphamoyl Carboxylic Acid Analogs

Compounds bearing and amino acid moieties are considered the basis for sulfa drug development. The synthesis of 4-methylphenylsulphamoyl acids and the evaluation of their pharmacological activities are reported. The synthesis of these compounds was accomplished by the reaction of various acids and 4-methyl chloride in basic aqueous solution. Structures were confirmed by FTIR, 1HNMR, 13CNMR spectra and elemental analytical data. Molecular docking interactions of the analogues were determined using PyRx. In the in antimicrobial activity analysis, compounds 1, 3, 5and 7 had antimicrobial inhibitory concentration range of 0.5-1.0mg/ml comparable with 0.1-2.0mg/ml of and . In the in anti-oxidant activity study compounds 1, 2and 6displayed half-maximal inhibitory concentrations (IC50) of 1.104±0.001 /ml, 1.159±0.002µg/ml and1.240±0.001µg/ml respectively comparable with 0.999±0.002µg/ml of acid. In the molecular docking study, compound 4 had a strong 2D binding interaction with II amino acid residue and compounds 1, 3, 4, 5, 6 and 7 had in antimicrobial, anti-oxidant, and antimalarial properties similar to their standard drugs. Considering the outstanding pharmacological properties and their strict compliance with Lipinski’s rule, the synthesized 4-methylphenylsulphamoyl analogues could be considered as antimicrobial, antimalarial, and anti-oxidant drug candidates.

Microwave‐assisted Synthesis and Molecular Docking Study of Heteroaromatic Chalcone Derivatives as Potential Antibacterial Agents

In this study, a series of chalcone derivatives (1a–c) were synthesized via Claisen‐Schmidt condensation, followed by aza‐Michael addition to form pyrazoline derivatives (2a–c and 3a–c). The reaction was performed via microwave radiation to give excellent yields (77–93%) in 1–3.5 min. Microwave‐assisted reaction of Fischer esterification of pyrazolines (2a–c and 3a–c) afforded heteroaromatic pyrazoline esters (4a–c) in high yield (83–96% in <2 min) compared to conventional reflux (55–79% in 30 min). Compounds 1a–c and 3a–c demonstrated excellent antibacterial activity against Staphylococcus aureus via disc diffusion assay with inhibition zone with 13 and 19 mm compared to a standard drug, ampicillin (11 mm). Structure activity relationship of 1b and 3b were visualized via molecular docking interaction against 4pql protein of S. aureus with binding free energy −7.0 and −8.0 kcal/mol, respectively. This study is significant in drug discovery process particularly for pharmaceutical industries.

A potential therapeutic effect of catalpol in Duchenne muscular dystrophy revealed by binding with TAK1.

BackgroundDuchenne muscular dystrophy (DMD) is a progressive muscle disease caused by the loss of dystrophin, which results in inflammation, fibrosis, and the inhibition of myoblast differentiation in skeletal muscle. Catalpol, an iridoid glycoside, improves skeletal muscle function by enhancing myogenesis; it has potential to treat DMD. We demonstrate the positive effects of catalpol in dystrophic skeletal muscle.Methods mdx (loss of dystrophin) mice (n = 18 per group) were treated with catalpol (200 mg/kg) for six consecutive weeks. Serum analysis, skeletal muscle performance and histology, muscle contractile function, and gene and protein expression were performed. Molecular docking and ligand–target interactions, RNA interference, immunofluorescence, and plasmids transfection were utilized to explore the protective mechanism in DMD by which catalpol binding with transforming growth factor‐β–activated kinase 1 (TAK1) in skeletal muscle.ResultsSix weeks of catalpol treatment improved whole‐body muscle health in mdx mice, which was characterized by reduced plasma creatine kinase (n = 18, −35.1%, P < 0.05) and lactic dehydrogenase (n = 18, −10.3%, P < 0.05) activity. These effects were accompanied by enhanced grip strength (n = 18, +25.4%, P < 0.05) and reduced fibrosis (n = 18, −29.0% for hydroxyproline content, P < 0.05). Moreover, catalpol treatment protected against muscle fatigue and promoted muscle recovery in the tibialis anterior (TA) and diaphragm (DIA) muscles (n = 6, +69.8%, P < 0.05 and + 74.8%, P < 0.001, respectively), which was accompanied by enhanced differentiation in primary myoblasts from DMD patients (n = 6, male, mean age: 4.7 ± 1.9 years) and mdx mice. In addition, catalpol eliminated p‐TAK1 overexpression in mdx mice (n = 12, −21.3%, P < 0.05) and primary myoblasts. The catalpol‐induced reduction in fibrosis and increased myoblast differentiation resulted from the inhibition of TAK1 phosphorylation, leading to reduced myoblast trans‐differentiation into myofibroblasts. Catalpol inhibited the phosphorylation of TAK1 by binding to TAK1, possibly at Asp‐206, Thr‐208, Asn‐211, Glu‐297, Lys‐294, and Tyr‐293.ConclusionsOur findings show that catalpol and TAK1 inhibitors substantially improve whole‐body muscle health and the function of dystrophic skeletal muscles and may provide a novel therapy for DMD.

Structure activity study of S-trityl-cysteamine dimethylaminopyridine derivatives as SIRT2 inhibitors: Improvement of SIRT2 binding and inhibition

Sirtuin proteins are a highly conserved class of nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacylases. The pleiotropic human isoform 2 of Sirtuins (SIRT2) has been engaged in the pathogenesis of cancer in a plethora of reports around the globe. Thus, SIRT2 modulation is deemed as a promising approach for pharmaceutical intervention. Previously, we reported S-Trityl-l-Cysteine (STLC)-ornamented dimethylaminopyridine chemical entity named STC4 with a significant SIRT2 inhibitory capacity; this was separate from the conventional application of STLC scaffold as a kinesin-5 inhibitor. An interactive molecular docking study of SIRT2 and STC4 showed interaction between Asn168 of SIRT2 and the methyl ester of STC4, that appears to hinder STC4 to reach the selective pocket of the protein unlike strong SIRT2 inhibitor SirReal2. To improve its activity, herein, we utilized S-trityl cysteamine pharmacophore lacking the methyl ester. Nine compounds were synthesized and assayed affording three biopertinent SIRT2 inhibitors, and two of them, STCY1 and STCY6 showed higher inhibitory activity than STC4. These compounds have pronounced anti-proliferative activities against different cancer cell lines. A molecular docking study was executed to shed light on the supposed binding mode of the lead compound, STCY1, into the selective pocket of SIRT2 by interaction of the nitrogen of pyridine ring of the compound and Ala135 of the protein. The outcome of the study exposes that the active compounds are effective intermediates to construct more potent biological agents.

Synthesis, spectroscopic characterization, molecular docking, and ADMET studies of mannopyranoside esters as antimicrobial agents

Regioselective unimolar one-step hexanoylation of methyl α-d-mannopyranoside (MDM) under controlled conditions furnished the 6-O-hexanoate and indicated the regioselectivity at C-6 position. To develop mannopyranoside based potential antimicrobial sugar esters (SEs), 6-O-hexanoate was further converted into five newer 2,3,4-tri-O-acyl esters reasonably in good yields. Both prediction of activity spectra for substances (PASS) and in vitro antimicrobial evaluation established these SEs as better antifungal agents than as antibacterials. Quantum chemical study has been performed to calculate the thermodynamic, molecular orbital and electrostatic potential properties. Molecular docking and nonbonding interactions have been performed against lanosterol 14α-demethylase (CYP51A1), A. flavus (1R51), and E. coli (4XO8) to search the binding affinity and interactions of MDM esters with the receptor proteins. ADMET prediction also performed to evaluate the absorption, metabolism, and toxic properties of SEs. Structure activity relationship (SAR) study along with in vitro, and in silico results indicated that amongst the acyl chains, caproic chain (C6) in combination with acetic (C2), caprylic (C8) or lauric (C12) chains were found the most promising against fungal pathogens.

Molecular docking analysis of piperine with CDK2,CDK4,Cyclin D and Cyclin T proteins.

Piperine is a component of Piper nigrum (Black pepper). It is well known in ayurvedic formulations. Piperine is a bioenhancer as it reduces the activity of drug-metabolizing enzymes in rodents and thereby enhancing the plasma concentrations of several drugs, including the Pglycoprotein substrates. Therefore, it is of interest to understand the molecular docking interactions of piperine with several cell cycle proteins such as Cyclin dependent kinase 2 (CDK2), Cyclin-dependent kinase 4 (CDK4), Cyclin D and Cyclin T for further consideration in drug discovery related to oral cancer.