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The emergence of hybrid imaging, combining anatomical computed tomography (CT) and functional scintigraphic imaging has increased the armoury of techniques available to image disease. Single photon emission computed tomography/CT (SPECT/CT) is a dual modality technique which increases the sensitivity and specificity of existing radionuclide imaging and helps characterise equivocal lesions detected by other imaging methods. In addition to the many established clinical applications for SPECT/CT, there are new clinical uses emerging in a spectrum of benign and malignant diseases. In this article, we will discuss the established and emerging uses of hybrid SPECT/CT and illustrate the incremental value of the technique in a variety of clinical applications. [ABSTRACT FROM AUTHOR]

Peptide- and protein-based therapeutics are becoming a promising treatment regimen for myriad diseases. Toxicity of proteins is the primary hurdle for protein-based therapies. Thus, there is an urgent need for accurate in silico methods for determining toxic proteins to filter the pool of potential candidates. At the same time, it is imperative to precisely identify non-toxic proteins to expand the possibilities for protein-based biologics. To address this challenge, we proposed an ensemble framework, called VISH-Pred, comprising models built by fine-tuning ESM2 transformer models on a large, experimentally validated, curated dataset of protein and peptide toxicities. The primary steps in the VISH-Pred framework are to efficiently estimate protein toxicities taking just the protein sequence as input, employing an under sampling technique to handle the humongous class-imbalance in the data and learning representations from fine-tuned ESM2 protein language models which are then fed to machine learning techniques such as Lightgbm and XGBoost. The VISH-Pred framework is able to correctly identify both peptides/proteins with potential toxicity and non-toxic proteins, achieving a Matthews correlation coefficient of 0.737, 0.716 and 0.322 and F1-score of 0.759, 0.696 and 0.713 on three non-redundant blind tests, respectively, outperforming other methods by over $10\%$ on these quality metrics. Moreover, VISH-Pred achieved the best accuracy and area under receiver operating curve scores on these independent test sets, highlighting the robustness and generalization capability of the framework. By making VISH-Pred available as an easy-to-use web server, we expect it to serve as a valuable asset for future endeavors aimed at discerning the toxicity of peptides and enabling efficient protein-based therapeutics., (© The Author(s) 2024. Published by Oxford University Press.)

Phyllanthus emblica L. (syn. Emblica officinalis), popularly known as amla, Indian gooseberry, or the King of Rasyana, is a member of Phyllanthaceae family and is traditionally used in Ayurveda as an immunity booster. The present study aimed to investigate the synergistic interaction of Phyllanthus emblica (FPE) fruits and its selected phytocompounds with ampicillin against selected bacteria. Further, an in silico technique was used to find if major phytocompounds of FPE could bind to proteins responsible for antibiotic resistance in bacterial pathogens and enhance the bioactivity of ampicillin. FPE and all the selected phytocompounds were found to have synergistic antibacterial activity with ampicillin against tested bacteria in different combinations. However, ellagic acid and quercetin interactions with ampicillin resulted in maximum bioactivity enhancement of 32-128 folds and 16-277 folds, respectively. In silico analysis revealed strong ellagic acid, quercetin, and rutin binding with penicillin-binding protein (PBP-) 3, further supported by MD simulations. Ellagic acid and quercetin also fulfill Lipinski's rule, showing similar toxicity characteristics to ampicillin. FPE showed synergistic interaction with ampicillin, possibly due to the presence of phytocompounds such as gallic acid, ellagic acid, quercetin, and rutin. Molecular docking and MD simulations showed the strong interaction of ellagic acid and quercetin with PBP-3 protein. Therefore, these compounds can be explored as potential non-toxic drug candidates to combat bacterial antimicrobial resistance., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Diversely functionalized pyrazolo-pyridine fused tetrazolo-pyrimidines 10aa-am and 10ba-bn were successfully synthesized via a catalyst-free synthetic protocol with moderate to very good yields. The compounds were evaluated for cytotoxicity against MCF-7 and HEK-293 cells using MTT assay. Among the tested compounds, 10ab (IC 50 - 23.83 µM) and 10ah (IC 50 - 23.30 µM) demonstrated the highest potency against MCF-7 cells, while 10bc (IC 50 - 14.46 µM) and 10bh (IC 50 - 2.53 µM) exhibited excellent cytotoxicity against HEK-293 cells. Additionally, antibacterial screening was performed against three Gram-negative bacteria ( E. coli, P. aeruginosa, and S. enterica ) and three Gram-positive bacteria ( S. aureus, B. megaterium, and B. subtilis ) using broth dilution method, while antifungal activity was assessed against three fungal strains ( A. niger, Penicillium, and S. cerevisiae ) using agar well diffusion method. In antimicrobial screening, the majority of the compounds demonstrated significant antibacterial efficacy compared to antifungal activity. We also conducted comprehensive computational studies, including DFT calculations, molecular docking and dynamics, and drug-likeness assessments. In the DFT study, compounds 10ac and 10bc displayed stable conformations, indicating their potential for higher therapeutic activity. Molecular docking analyses revealed compelling interactions, with compound 10ah demonstrating docking score -7.42 kcal/mol against catalytical domain PARP1 (PDB ID: 7KK4) and 10bh exhibiting a best docking score -10.77 kcal/mol against human corticotropin-releasing factor receptor 1 (PDB ID: 4Z9G). A 100 ns molecular dynamics (MD) simulation study of compounds 10ah and 10bh revealed the stable conformation and binding energy in a stimulating environment. In drug-likeness assessments, both the compounds 10ah and 10bh adhere all the established guidelines.Communicated by Ramaswamy H. Sarma.

In recent years, due to the dramatic increase of the bacteria resistance to antibiotics and chemotherapeutic drugs, an increasing importance is given to the discovery of novel bioactive molecules, more potent than those in use. In this contest, methanol extracts of different parts of the medicinal plant Limoniastrum monopetalum (L.) Boiss. (Plumbaginaceae), widely occurring in Tunisia, were prepared to evaluate the antimicrobial and antiproliferative activities. The methanol extract of the roots showed the highest antibacterial activity against E. coli, S. aureus and E. faecalis, whereas the stem extract exhibited the highest antiproliferative effects towards a Hela cell line. Analysis of volatile fractions, using gas chromatography-mass spectrometry (GC-MS) and gas chromatography-flame ionization detector (GC-FID) techniques, led to the identification of camphor as the most abundant constituent, which represented from 84.85 to 99.48% of the methanol extracts. Multiple chromatographic separation of the methanol leaf extract afforded the flavonoid maeopsin-6-O-glucoside (S1) and a few fractions that were subjected to biological activity assays. One fraction exhibited interesting antibacterial activity against E. coli and E. faecalis (MIC values of 62.5 and 78.12 µg/mL, respectively), and antiproliferative effects against Hela and A549 cells (IC 50  = 226 and 242.52 μg/mL, respectively). In addition, in silico studies indicated that maesopsin-6-O-glucoside, which was moderately active against Staphylococcus aureus, strongly interacted with the active site of the accessory gene regulator protein A (AgrA) of Staphylococcus aureus., (© 2023. The Author(s).)

The detection of trace amounts of sulfosulfuron, a pesticide of increasing importance, has become a pressing issue, prompting the development of effective chemosensors. In this study, we functionalized cyclotricatechylene (CTC) with propyl-phthalimide due to the presence of electronegative oxygen and nitrogen binding sites. Our optimized ligand displayed the highest docking score with sulfosulfuron, and experimental studies confirmed a significant fluorescence enhancement upon its interaction with sulfosulfuron. To gain a deeper understanding of the binding mechanism, we introduced density functional theory (DFT) studies. We carried out binding constant, Job's plot, and limit of detection (LOD) calculations to establish the effectiveness of our chemosensor as a selective detector for sulfosulfuron. These findings demonstrate the potential of our chemosensor for future applications in the field of pesticide detection., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Introduction: IL-13 is the primary upregulated cytokine in atopic dermatitis (AD) skin and is the pathogenic mediator driving AD pathophysiology. Lebrikizumab, tralokinumab and cendakimab are therapeutic monoclonal antibodies (mAb) that target IL-13., Methods: We undertook studies to compare in vitro binding affinities and cell-based functional activities of lebrikizumab, tralokinumab and cendakimab., Results: Lebrikizumab bound IL-13 with higher affinity (as determined using surface plasma resonance) and slower off-rate. It was more potent in neutralizing IL-13-induced effects in STAT6 reporter and primary dermal fibroblast periostin secretion assays than either tralokinumab or cendakimab. Live imaging confocal microscopy was employed to determine the mAb effects on IL-13 internalization into cells via the decoy receptor IL-13Rα2, using A375 and HaCaT cells. The results showed that only the IL-13/lebrikizumab complex was internalized and co-localized with lysosomes, whereas IL-13/tralokinumab or IL-13/cendakimab complexes did not internalize., Conclusion: Lebrikizumab is a potent, neutralizing high-affinity antibody with a slow disassociation rate from IL-13. Additionally, lebrikizumab does not interfere with IL-13 clearance. Lebrikizumab has a different mode of action to both tralokinumab and cendakimab, possibly contributing to the clinical efficacy observed by lebrikizumab in Ph2b/3 AD studies., (© 2023. The Author(s).)

Potentilla nepalensis Hook is a perennial Himalayan medicinal herb of the Rosaceae family. The present study aimed to evaluate biological activities such as the antioxidant, antibacterial, and anticancer activities of roots and shoots of P. nepalensis and its synergistic antibacterial activity with antibacterial drugs. Folin-Ciocalteau and aluminium chloride methods were used for the calculation of total phenolic (TPC) and flavonoid content (TFC). A DPPH radical scavenging assay and broth dilution method were used for the determination of the antioxidant and antibacterial activity of the root and shoot extracts of P. nepalensis . Cytotoxic activity was determined using a colorimetric MTT assay. Further, phytochemical characterization of the root and shoot extracts was performed using the Gas chromatography-mass spectrophotometry (GC-MS) method. The TPC and TFC were found to be higher in the methanolic root extract of P. nepalensis . The methanolic shoot extract of P. nepalensis showed good antioxidant activity, while then-hexane root extract of P. nepalensis showed strong cytotoxic activity against tested SK-MEL-28 cells. Subsequently, in silico molecular docking studies of the identified bioactive compounds predicted potential anticancer properties. This study can lead to the production of new herbal medicines for various diseases employing P. nepalensis , leading to the creation of new medications.

Monkeypox virus (MPXV) was confirmed in May 2022 and designated a global health emergency by WHO in July 2022. MPX virions are big, enclosed, brick-shaped, and contain a linear, double-stranded DNA genome as well as enzymes. MPXV particles bind to the host cell membrane via a variety of viral-host protein interactions. As a result, the wrapped structure is a potential therapeutic target. DeepRepurpose, an artificial intelligence-based compound-viral proteins interaction framework, was used via a transfer learning setting to prioritize a set of FDA approved and investigational drugs which can potentially inhibit MPXV viral proteins. To filter and narrow down the lead compounds from curated collections of pharmaceutical compounds, we used a rigorous computational framework that included homology modeling, molecular docking, dynamic simulations, binding free energy calculations, and binding pose metadynamics. We identified Elvitegravir as a potential inhibitor of MPXV virus using our comprehensive pipeline., Competing Interests: Conflicts of Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Terminalia arjuna (Roxb. ex DC.) Wight & Arnot of the Combretaceae family is one of the most frequently approved and utilized medicinal trees in the traditional medicinal system, which was used for the treatment of a variety of diseases, including cardiovascular disorders. The present study aims to identify phytochemicals from T. arjuna , that do not exhibit any toxicity and have significant cardioprotective activity using an in-silico technique. Four different cardiovascular proteins, namely human angiotensin receptor (PDB ID: 4YAY), P38 mitogen-activated protein kinase (MAPK, PDB ID: 4DLI), 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-Co A) reductase (PDB ID: 1HW9), and human C-reactive protein (PDB ID: 1B09), were used as target proteins to identify potential inhibitors using a virtual screening of the phytochemicals in T. arjuna revealed casuarinin as a potential inhibitor of all selected target proteins with strong binding energy. Furthermore, MD simulations for a 100 ns time scale also revealed that most of the key protein contacts of all target proteins were retained throughout the simulation trajectories. Binding free energy calculations using the MM-GBSA approach also support a strong inhibitory effect of casuarinin on target proteins. Casuarinin's effective binding to these proteins lays the groundwork for the development of broad-spectrum drugs as well as the understanding of the underlying mechanism against cardiovascular diseases through in vivo and clinical studies.

SARS-CoV-2 has mutated many times among different populations. We analyzed wild-type spike protein and 18 different variants of SARS-CoV-2 spike protein known until the beginning of 2022 (alpha, beta, B.1.429, B.1.616, B.1.620, B.1.617.3, C.1.2, delta, epsilon, eta, gamma, iota, kappa, lambda, mu, omicron, theta, and zeta) for their interaction with 16 phytocompounds and remdesivir, resulting into 425 combinations. The largest number of mutations has been reported in the omicron followed by delta variant. However, the virulence of the delta variant has been reported higher as compared to omicron. Mutations at a few locations (D215G, K417N, E484K, N501Y, D614G, and P681H) were common in most of the variants. 3 D structures of all the 18 spike proteins were created using SWISS-MODEL to test the binding affinities with caffeine theophylline, emodin, vitexin, berberine, curcumin, piperine, quercetin, artemisinin, carvacrol, capsaicin, tetrahydrocannabinol, cannabidiol, α- pinene, β- pinene and gingerol. Phytocompounds and mutant variants were prepared using AutoDock 4.2.6 software. Binding affinities of the selected phytocompounds with the different mutant spike proteins were achieved using AutoDock Vina. Out of all combinations investigated, the best binding affinities were observed with 3 variants of SAR-CoV-2 with 5 phytocompounds along with remdesivir. The range of best binding energies varied from -9.1 to -8.0 kcal/mol. Further, MD simulation was done for selected 9 phytocompound-spike mutant complexes for analyzing the stability of interactions for 100 ns. ADMET studies via ProTox-II and SwissADME displayed that phytocompounds are safe and less toxic in comparison to remdesivir.Communicated by Ramaswamy H. Sarma.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is significantly impacting human lives, overburdening the healthcare system and weakening global economies. Plant-derived natural compounds are being largely tested for their efficacy against COVID-19 targets to combat SARS-CoV-2 infection. The SARS-CoV-2 Main protease (M pro ) is considered an appealing target because of its role in replication in host cells. We curated a set of 7809 natural compounds by combining the collections of five databases viz Dr Duke's Phytochemical and Ethnobotanical database, IMPPAT, PhytoHub, AromaDb and Zinc. We applied a rigorous computational approach to identify lead molecules from our curated compound set using docking, dynamic simulations, the free energy of binding and DFT calculations. Theaflavin and ginkgetin have emerged as better molecules with a similar inhibition profile in both SARS-CoV-2 and Omicron variants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Essential oils (EOs) have gained immense popularity due to considerable interest in the health, food, and pharmaceutical industries. The present study aimed to evaluate the antimicrobial and antioxidant activity and the anti-diabetic potential of Curcuma longa leaf (CLO) essential oil. Further, major phytocompounds of CLO were analyzed for their in-silico interactions with antifungal, antioxidant, and anti-diabetic proteins. CLO was found to have a strong antifungal activity against the tested Candida species with zone of inhibition (ZOI)-11.5 ± 0.71 mm to 13 ± 1.41 mm and minimum inhibitory concentration (MIC) was 0.63%. CLO also showed antioxidant activity, with IC 50 values of 5.85 ± 1.61 µg/mL using 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay and 32.92 ± 0.64 µM using ferric reducing antioxidant power (FRAP) assay. CLO also showed anti-diabetic activity with an IC 50 of 43.06 ± 1.24 µg/mL as compared to metformin (half maximal inhibitory concentration, IC 50 -16.503 ± 0.66 µg/mL). Gas chromatography-mass spectrometry (GC-MS) analysis of CLO showed the presence of (-)-zingiberene (17.84%); 3,7-cyclodecadien-1-one, 3,7-dimethyl-10-(1-methylethylidene)-(15.31%); cyclohexene, 4-methyl-3-(1-methylethylidene) (12.47%); and (+)-4-Carene (11.89%) as major phytocompounds. Molecular docking of these compounds with antifungal proteins (cytochrome P450 14 alpha-sterol demethylase, PDB ID: 1EA1, and N-myristoyl transferase, PDB ID: 1IYL), antioxidant (human peroxiredoxin 5, PDB ID: 1HD2), and anti-diabetic proteins (human pancreatic alpha-amylase, PDB ID: 1HNY) showed strong binding of 3,7-cyclodecadien-1-one with all the selected protein targets. Furthermore, molecular dynamics (MD) simulations for a 100 ns time scale revealed that most of the key contacts of target proteins were retained throughout the simulation trajectories. Binding free energy calculations using molecular mechanics generalized born surface area (MM/GBSA), and drug-likeness and toxicity analysis also proved the potential for 3,7-cyclodecadien-1-one, 3,7-dimethyl-10-(1-methylethylidene) to replace toxic synthetic drugs and act as natural antioxidants.

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

Hypertension has been a significant cause of death due to elevated blood pressure worldwide. The results of molecular docking showed out of selected 40 compounds, chasmanthin (-11.05 kcal/mol), and palmarin (-11.22 kcal/mol) showed strong binding with angiotensin-converting enzyme (ACE) target. The inhibitory action of the selected phytocompounds for ACE protein was also validated by comparing it with the reference drugs, lisinopril (-9.42 kcal/mol), and enalapril (-5.07 kcal/mol). MD simulations study of 100 ns also demonstrated stability of chasmanthin, and palmarin within the active sites of ACE protein. Molecular mechanics generalised born surface area (MMGBSA) analysis of MD trajectories exhibited significant binding of palmarin with ACE (dG Bind= -38.65 ± 2.59 kcal/mol) and chasmanthin (dG Bind= -37.64 ± 2.67 kcal/mol). Drug likeness and pharmacokinetics properties of palmarin and chasmanthin was also found to be permissible, thereby suggesting the use of chasmanthin and palmarin as a novel target inhibitor against ACE protein to combat hypertension.

Institutional variations in parathyroid adenoma localisation are largely dictated by local experience and availability of imaging investigations, with no consensus on the optimal approach. This review evaluates the role of multiple imaging techniques in primary hyperparathyroidism and highlights their advantages and limitations in different clinical contexts. A clinico-radiological review of parathyroid imaging techniques is illustrated with example cases and data from the literature. These include high-resolution ultrasound, 99m Tc-sestamibi planar scintigraphy with and without thyroid subtraction techniques, integrated 99m Tc-sestamibi single-photon-emission computed tomography (SPECT)/computed tomography (CT), four-dimensional (4D) CT, and other techniques, such as magnetic resonance imaging, integrated 18 F-choline/ 11 C-methionine positron-emission tomography (PET)/CT and angiographic selective venous sampling. The crucial role of parathyroid embryological and gross anatomy in informing the surgical approach to parathyroidectomy is discussed. Finally, a systematic approach to imaging is proposed to maximise the accuracy of imaging localisation of parathyroid lesions, which is crucial for optimal patient management., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Structure-based pharmacophore models are often developed by selecting a single protein-ligand complex with good resolution and better binding affinity data which prevents the analysis of other structures having a similar potential to act as better templates. PharmRF is a pharmacophore-based scoring function for selecting the best crystal structures with the potential to attain high enrichment rates in pharmacophore-based virtual screening prospectively. The PharmRF scoring function is trained and tested on the PDBbind v2018 protein-ligand complex dataset and employs a random forest regressor to correlate protein pocket descriptors and ligand pharmacophoric elements with binding affinity. PharmRF score represents the calculated binding affinity which identifies high-affinity ligands by thorough pruning of all the PDB entries available for a particular protein of interest with a high PharmRF score. Ligands with high PharmRF scores can provide a better basis for structure-based pharmacophore enumerations with a better enrichment rate. Evaluated on 10 protein-ligand systems of the DUD-E dataset, PharmRF achieved superior performance (average success rate: 77.61%, median success rate: 87.16%) than Vina docking score (75.47%, 79.39%). PharmRF was further evaluated using the CASF-2016 benchmark set yielding a moderate correlation of 0.591 with experimental binding affinity, similar in performance to 25 scoring functions tested on this dataset. Independent assessment of PharmRF on 8 protein-ligand systems of LIT-PCBA dataset exhibited average and median success rates of 57.55% and 74.72% with 4 targets attaining success rate > 90%. The PharmRF scoring model, scripts, and related resources can be accessed at https://github.com/Prasanth-Kumar87/PharmRF., (© 2022 Wiley Periodicals LLC.)

Rheum emodi Wall. (Himalayan rhubarb) has many pharmacological activities such as antioxidant, antimicrobial, antiviral, anticancer and wound healing. The present study was aimed to understand if major phytocompounds of Rheum emodi could bind proteins responsible for antibiotic resistance in bacterial and fungal pathogens and enhance the potency of antibiotics. The major phytocompounds of R. emodi (emodin, rhein-13c6 and chrysophenol dimethy ether) were retrieved from the Pubchem and target proteins were retrieved from RCSB protein data bank. The docking study was performed by using AutoDock vina software and Molinspiration, swiss ADME servers were used for the determination of Lipinski rule of 5, drug-likeness prediction respectively, whereas, admetSAR and Protox-II tools were used for toxicity prediction. To study the docking accuracy of protein-ligand complexes, MD simulation for 100 ns was done by using Desmond program version 2.0 (Academic version). Among all the selected phytocompounds, emodin showed the best binding affinity against bacterial (Penicillin binding protein 3, 3VSL and fungal target (cytochrome P450 14 alpha-sterol demethylase 1EA1) with binding energy -8.2 and -8.0 Kcal mol -1 respectively. Similarly, rhein-13C6 showed the best binding affinity against fungal target (n-myristoyl transferase 1IYL) with binding energy -8.0 Kcal mol -1 which is higher than antibacterial and antifungal antibiotics. All the selected phytocompounds also fulfill Lipinski rule, non-carcinogenic and non-cytotoxic in nature. These compounds also showed high LD 50 value showing non-toxicity of these phytocompounds. MD simulation studies of phytocompounds (emodin and rhein-13C6) define the stability of protein-ligand complexes with in 100 ns time scale.Communicated by Freddie R. Salsbury.

Cymbopogon citratus (DC.) Stapf is an aromatic perennial herb of Gramineae (Poaceae) family and is known for its application in food and healthcare industry. The present study aimed to evaluate anti-inflammatory and antioxidant potential of C. citratus essential oil (CEO) through in vitro and in silico studies. Chemical characterization of CEO was done using Gas chromatography-mass spectrophotometry (GC-MS) method. In vitro antioxidant activity was evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2, 2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and ferric ion reducing antioxidant power (FRAP) assays, while egg albumin denaturation method was used to evaluate in vitro anti-inflammatory activity of CEO. Molecular docking investigation of major phytocompounds of CEO was done using Autodock vina software against human peroxiredoxin 5 (PDB ID: 1HD2) and human cyclooxygenase 2 (PDB ID: 5IKQ) proteins, which were further analyzed through molecular dynamics (MD) simulation using YASARA. GC-MS analysis of CEO showed the presence of geranial (48%) neral (34.04%), β-myrcene (9.77%), geraniol (1.88%), linalool (0.84%), isogeranial (0.81%), β-caryophyllene (0.80%), D-limonene (0.51%) as major constituents. CEO showed significant antioxidant activity with DPPH (IC 50 -47.53   ±   2.16   µg/ml), FRAP (IC 50 -30.7   ±   0.31   µM), and ABTS assays (IC 50 -27.87   ±   0.09   µg/ml). CEO also exhibited significant in-vitro anti-inflammatory activity with IC 50 -29.71   ±   1.95   µg/ml as compared to that of Diclofenac sodium (IC 50 -36.52   ±   1.95   µg/ml). Molecular docking revealed that β-caryophyllene showed considerable binding potential with human peroxiredoxin 5 receptor (-6.0   kcal/mol) and human cyclooxygenase 2 receptor (-10.1   kcal/mol). Further, MD simulations demonstrated considerable and stable interactions of β-caryophyllene with 1HD2 and 5IKQ proteins up to 100   ns. Drug-likeness and ADME/T features also showed that β-caryophyllene can be used as a potential candidate to replace the synthetic anti-inflammatory drugs with side effects and also act as natural antioxidants.Communicated by Ramaswamy H. Sarma.

Wild thyme ( Thymus serpyllum L.) of family Laminaceae is an unexplored perennial medicinal shrub. Aerial part of this plant is traditionally used for the treatment of respiratory and gastrointestinal problems. The current study was designed to evaluate the GC-MS, antimicrobial and synergistic potential of T. serpyllum essential oil (TEO). Chemical characterization of TEO showed the presence of thymol (15.79%), Phenol, 2-(1,1-dimethylethyl) (11.55%), o-Cymene (10.96%) as major phytocompounds. Antimicrobial activity of TEO in terms zone of inhibition (ZOI) varied from 13.66 ± 0.58 mm to 33.66 ± 1.52 mm, while, thymol (10%, v/v) showed ZOI ranged from 15.5 ± 0.5 mm to 26.33 ± 2.08 mm against tested bacterial and fungal species. MIC of TEO was 0.039% to 0.078% against tested bacterial and fungal species, whereas, thymol showed 1.25% to 2.5% MIC against tested bacterial and fungal species. Different combinations of TEO (2MIC to ½MIC) and thymol (2MIC to ½MIC) with antibacterial and antifungal antibiotics (2MIC to ½MIC) were found to increase the efficacy of antibiotics by 4-130 folds against bacterial and fungal pathogens. Molecular docking showed the good binding of thymol with both bacterial and fungal targets. Whereas MD simulation showed the stability of thymol complexed with target proteins over 100 ns time scale. Thymol also fulfills the Lipinski rule and showed characteristics similar to that of drugs. Therefore, it can be concluded from the present study that TEO and its major phytocompound, thymol can act as a bioactivity enhancer of antibacterial and antifungal antibiotics and could be used as a potential candidate to fight against antimicrobial drug resistance.Communicated by Ramaswamy H. Sarma.

The aim of the present study was to test the binding affinity of methylxanthines (caffeine/theine, methylxanthine, theobromine, theophylline and xanthine) to three potential target proteins namely Spike protein (6LZG), main protease (6LU7) and nucleocapsid protein N-terminal RNA binding domain (6M3M) of SARS-CoV-2. Proteins and ligand were generated using AutoDock 1.5.6 software. Binding affinity of methylxanthines with SARS-CoV-2 target proteins was determined using Autodock Vina. MD simulation of the best interacting complexes was performed using GROMACS 2018.3 (in duplicate) and Desmond program version 2.0 (academic version) (in triplicate) to study the stabile interaction of protein-ligand complexes. Among the selected methylxanthines, theophylline showed the best binding affinity with all the three targets of SARS-CoV-2 (6LZG - 5.7 kcal mol -1 , 6LU7 - 6.5 kcal mol -1 , 6M3M - 5.8 kcal mol -1 ). MD simulation results of 100 ns (in triplicate) showed that theophylline is stable in the binding pockets of all the selected SARS-CoV-2 proteins. Moreover, methylxanthines are safer and less toxic as shown by high LD 50 value with Protox II software as compared to drug chloroquine. This research supports the use of methylxanthines as a SARS-CoV-2 inhibitor. It also lays the groundwork for future studies and could aid in the development of a treatment for SARS-CoV-2 and related viral infections., Supplementary Information: The online version contains supplementary material available at 10.1007/s40495-021-00276-3., Competing Interests: Conflict of InterestThe authors declare that they have no competing interests., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022.)

Aim: To compare clinical performance and parental satisfaction with composite strip crown and prefabricated zirconia crown for primary anterior teeth., Materials and Methods: The study compares clinical evaluation and parental satisfaction of two different crowns for primary anterior teeth. A total of 102 teeth in each group selected between ages 3 and 6 years, who met the inclusion criteria, were randomly allocated into two groups for further evaluation. Group A for strip crowns (55 teeth) and group B for zirconia crowns (47 teeth). The crowns were evaluated clinically with various criteria like-color match, crown retention, gingival health, crown contour, opposing tooth wear, marginal integrity, and recurrent caries. The samples were also evaluated for parental satisfaction based on 5-point Likert scale and child liking was also recorded with Smiley face Likert scale at baseline, 3 and 9 months. Statistical analysis was done using Chi-square test ( p <0.05)., Results: Zirconia crowns showed better color match, crown retention, crown contour, and gingival health. Strip crowns showed more discoloration and chipping of material over a period of time. None of the samples showed opposing tooth wear, open margins, and recurrent caries in strip and zirconia crown group. Parents and children both were highly satisfied with zirconia crowns., Conclusion: Clinically zirconia crowns showed higher success rate as compared to strip crowns and parental overall satisfaction was higher for zirconia crowns., Clinical Significance: Zirconia crowns exhibited a higher clinical performance and parental satisfaction; hence, if affordability is out weighted, zirconia crown stands better with esthetics of the child.

Novel SARS-CoV-2, an etiological factor of Coronavirus disease 2019 (COVID-19), poses a great challenge to the public health care system. Among other druggable targets of SARS-Cov-2, the main protease (M pro ) is regarded as a prominent enzyme target for drug developments owing to its crucial role in virus replication and transcription. We pursued a computational investigation to identify M pro inhibitors from a compiled library of natural compounds with proven antiviral activities using a hierarchical workflow of molecular docking, ADMET assessment, dynamic simulations and binding free-energy calculations. Five natural compounds, Withanosides V and VI, Racemosides A and B, and Shatavarin IX, obtained better binding affinity and attained stable interactions with M pro key pocket residues. These intermolecular key interactions were also retained profoundly in the simulation trajectory of 100 ns time scale indicating tight receptor binding. Free energy calculations prioritized Withanosides V and VI as the top candidates that can act as effective SARS-CoV-2 M pro inhibitors., (© 2021. The Author(s).)

Since December 2019, coronavirus disease (COVID-19) has claimed the lives of millions of people across the globe. To date, no medicine is available for the responsible virus SARS-CoV-2. 3CLpro, that is, 3-chymotrypsin-like protease, the main protease (M pro ), has an important role in cleaving pp1a and pp1ab polyproteins. This M pro serves as an important target in drug designing against COVID-19. Herein, the study includes the investigation, screening, and identification of potent leads from (Withania sps.), against SARS-CoV-2, using virtual screening, molecular docking, and molecular dynamics (MD) simulations. Seventy-three natural compounds from this important medicinal plant were screened. The Binding affinity was used to identify the most probable target to inhibit the M pro , compounds 27-hydroxywithanolide F (W32, -11.5 kcal/mol), withanolide A (W56, -11.4 kcal/mol), and withacoagulin H (W30, -11.1 kcal/mol) showed highest binding energy. Lipinski's rule, followed by drug-likability and likeness screening, resulted in 36 molecules. Further, MD simulation of 50 ns predicted withacoagulin H possessing strong binding affinity and hydrogen-bonding interactions with the active site. The binding free energy calculation showed the most negative energy of withacoagulin H (-63.463 KJ/mol) compared to other selected compounds. The study also compared the bonding energy of already reported repurposed and newly synthesized drugs. Further, absorption, distribution, metabolism, and excretion predictions were made to found a good balance of potency. Hence the following screened compounds from Withania sps. could serve as the potential leads for drug development against COVID-19., (© 2021 Wiley Periodicals LLC.)

SARS-CoV-2, the viral particle, is responsible for triggering the 2019 Coronavirus disease outbreak (COVID-19). To tackle this situation, a number of strategies are being devised to either create an antidote, a vaccine, or agents capable of preventing its infection. To enable research on these strategies, numerous target proteins are identified where Spike (S) protein is presumed to be of immense potential. S-protein interacts with human angiotensin-converting-enzyme-2 (ACE2) for cell entry. The key region of S-protein that interacts with ACE2 is a portion of it designated as a receptor-binding domain (RBD), following whereby the viral membrane fuses with the alveolar membrane to enter the human cell. The proposition is to recognize molecules from the bundle of phytochemicals of medicinal plants known to possess antiviral potentials as a lead that could interact and mask RBD, rendering them unavailable to form ACE2 interactions. Such a molecule is called the 'S-protein blocker'. A total of 110 phytochemicals from Withania somnifera, Asparagus racemosus, Zinziber officinalis, Allium sativum, Curcuma longa and Adhatoda vasica were used in the study, of which Racemoside A, Ashwagandhanolide, Withanoside VI, Withanoside IV and Racemoside C were identified as top five hits using molecular docking. Further, essential Pharmacophore features and their ADMET profiles of these compounds were studied following to which the best three hits were analyzed for their interaction with RBD using Molecular Dynamics (MD) simulation. Binding free energy calculations were performed using MM/GBSA, proving these phytochemicals can serve as S-protein blocker., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The pandemic outbreak of the Corona viral infection has become a critical global health issue. Biophysical and structural evidence shows that spike protein possesses a high binding affinity towards host angiotensin-converting enzyme 2 and viral hemagglutinin-acetylesterase (HE) glycoprotein receptor. We selected HE as a target in this study to identify potential inhibitors using a combination of various computational approaches such as molecular docking, ADMET analysis, dynamics simulations and binding free energy calculations. Virtual screening of NPACT compounds identified 3,4,5-Trihydroxy-1,8-bis[(2R,3R)-3,5,7-trihydroxy-3,4-dihydro-2H-chromen-2-yl]benzo[7]annulen-6-one, Silymarin, Withanolide D, Spirosolane and Oridonin as potential HE inhibitors with better binding energy. Furthermore, molecular dynamics simulations for 100 ns time scale revealed that most of the key HE contacts were retained throughout the simulations trajectories. Binding free energy calculations using MM/PBSA approach ranked the top-five potential NPACT compounds which can act as effective HE inhibitors.

Introduction: Histamine, a biological amine, is considered as a principal mediator of many pathological processes regulating several essential events in allergies and autoimmune diseases. Numerous derivatives have been developed that strive with histamine at the H1 receptor and prevent binding of histamine at the H1 receptor, thereby preventing allergic reactions. Molecules containing a triazole ring fused with six-membered ring systems are found to possess broad applications in the field of medicine and industry. The present study is an attempt to characterize the impact of the nature of the substituent introduced at 5 positions of the-4H-1,2,4-triazole-3-thiol on their capacities to bind with the H1 receptor., Methods: Molecular docking (PDB ID: 3RZE) revealed that synthesized derivatives and target proteins were actively involved in binding with Tyr-108, Thr-112, Ala-216, and Phe-432 subunits. A pharmacophore model, new 5-(4-substituted phenyl)-4-(phenylamino)-4-H-1,2,4-triazole-3- thiols (5a-5h) were designed and evaluated for H1-blocking activity using isolated segments from the guinea pig ileum., Results: According to in silico analysis, all the compounds have a topological polar surface area (TPSA) less than 140 Å squared, so they tend to easily penetrate cell membranes. The results show that most of the compounds are non-inhibitors of CYP450 substrates that play a fundamental role in drug metabolism. Compounds 5d (50.53±12.03), 5h (50.62±12.33) and 7a (55.07±12.41) are more active than others., Conclusion: Finally, these derivatives were screened for H1 receptor antagonist activity using guinea pig ileum, taking chlorpheniramine maleate as a standard. Most of the compounds were found to possess better antihistamine activity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Receptor-based QSAR approaches can enumerate the energetic contributions of amino acid residues toward ligand binding only when experimental binding affinity is associated. The structural data of protein-ligand complexes are witnessing a tremendous growth in the Protein Data Bank deposited with a few entries on binding affinity. We present here a new approach to compute the Energetic CONTributions of Amino acid residues and its possible Cross-Talk (ECONTACT) to study ligand binding using per-residue energy decomposition, molecular dynamics simulations and rescoring method without the need for experimental binding affinity. This approach recognizes potential cross-talks among amino acid residues imparting a nonadditive effect to the binding affinity with evidence of correlative motions in the dynamics simulations. The protein-ligand interaction energies deduced from multiple structures are decomposed into per-residue energy terms, which are employed as variables to principal component analysis and generated cross-terms. Out of 16 cross-talks derived from eight datasets of protein-ligand systems, the ECONTACT approach is able to associate 10 potential cross-talks with site-directed mutagenesis, free energy, and dynamics simulations data strongly. We modeled these key determinants of ligand binding using joint probability density function (jPDF) to identify cross-talks in protein structures. The top two cross-talks identified by ECONTACT approach corroborated with the experimental findings. Furthermore, virtual screening exercise using ECONTACT models better discriminated known inhibitors from decoy molecules. This approach proposes the jPDF metric to estimate the probability of observing cross-talks in any protein-ligand complex. The source code and related resources to perform ECONTACT modeling is available freely at https://www.gujaratuniversity.ac.in/econtact/., (© 2020 Wiley Periodicals, Inc.)

Background: The rapidly enlarging COVID-19 pandemic caused by the novel SARS-corona virus-2 is a global public health emergency of an unprecedented level. Unfortunately no treatment therapy or vaccine is yet available to counter the SARS-CoV-2 infection, which substantiates the need to expand research efforts in this direction. The indispensable function of the main protease in virus replication makes this enzyme a promising target for inhibitors screening and drug discovery to treat novel coronavirus infection. The recently concluded α-ketoamide ligand-bound X-ray crystal structure of SARS-CoV-2 M pro (PDB ID: 6Y2F) from Zhang et al. has revealed the potential inhibitor binding mechanism and the molecular determinants responsible for substrate binding., Methods: For the study, we have targeted the SARS-CoV-2 M pro for the screening of FDA approved antiviral drugs and carried out molecular docking based virtual screening. Further molecular dynamic simulation studies of the top three selected drugs carried out to investigated for their binding affinity and stability in the SARS-CoV-2 M pro active site. The phylogenetic analysis was also performed to know the relatedness between the SARS-CoV-2 genomes isolated from different countries., Results: The phylogenetic analysis of the SARS-CoV-2 genome reveals that the virus is closely related to the Bat-SL-CoV and does not exhibit any divergence at the genomic level. Molecular docking studies revealed that among the 77 drugs, screened top ten drugs shows good binding affinities, whereas the top three drugs: Lopinavir-Ritonavir, Tipranavir, and Raltegravir were undergone for molecular dynamics simulation studies for their conformational stability in the active site of the SARS-CoV-2 M pro protein., Conclusions: In the present study among the library of FDA approved antiviral drugs, the top three inhibitors Lopinavir-Ritonavir, Tipranavir, and Raltegravir show the best molecular interaction with the main protease of SARS-CoV-2. However, the in-vitro efficacy of the drug molecules screened in this study further needs to be corroborated by carrying out a biochemical and structural investigation., (Copyright © 2020. Published by Elsevier Ltd.)

The assessment of major organ toxicities through in silico predictive models plays a crucial role in drug discovery. Computational tools can predict chemical toxicities using the knowledge gained from experimental studies which drastically reduces the attrition rate of compounds during drug discovery and developmental stages. The purpose of in silico predictions for drug leads and anticipating toxicological endpoints of absorption, distribution, metabolism, excretion and toxicity, clinical adverse impacts and metabolism of pharmaceutically active substances has gained widespread acceptance in academia and pharmaceutical industries. With unrestricted accessibility to powerful biomarkers, researchers have an opportunity to contemplate the most accurate predictive scores to evaluate drug's adverse impact on various organs.A multiparametric model involving physico-chemical properties, quantitative structure-activity relationship predictions and docking score was found to be a more reliable predictor for estimating chemical toxicities with potential to reflect atomic-level insights. These in silico models provide informed decisions to carry out in vitro and in vivo studies and subsequently confirms the molecules clues deciphering the cytotoxicity, pharmacokinetics, and pharmacodynamics and organ toxicity properties of compounds. Even though the drugs withdrawn by USFDA at later phases of drug discovery which should have passed all the state-of-the-art experimental approaches and currently acceptable toxicity filters, there is a dire need to interconnect all these molecular key properties to enhance our knowledge and guide in the identification of leads to drug optimization phases. Current computational tools can predict ADMET and organ toxicities based on pharmacophore fingerprint, toxicophores and advanced machine-learning techniques.

Purpose: To test the reliability and accuracy of a standardised non-invasive imaging algorithm using optical coherence tomography angiography (OCTA) in detecting and quantifying pharmacologically induced changes in the perilimbal vasculature., Methods: In this prospective observational imaging study, 370 angiograms of 15 normal eyes and 10 eyes with nasal pterygiums were obtained using a commercially available OCTA system with split-spectrum amplitude-decorrelation angiography technology. Postprocessing of the images to quantify the area occupied by the blood vessels was performed using the Fiji software. The main outcome measures were reliability (intraobserver and interobserver agreement) and accuracy of the standardised algorithm in detecting and quantifying relative change (vasoconstriction and vasodilatation) in the area occupied by the blood vessels after instillation of topical vasoconstrictors., Results: The intraclass correlation coefficients for intraobserver and interobserver agreement were 0.91 and 0.88 (good to excellent), respectively. In normal eyes, significant vasoconstriction was noted at 5 min (35%-47%) after application of eye-drops, which peaked at 10 min (43%-63%) and was sustained until 20 min (35%-51%), followed by gradual recovery. Greatest effect was noted with a combination of 5% phenylephrine and 0.15% brimonidine tartrate (BT) eye-drops as compared with either one or two drops of BT alone, both at the 10 min (p=0.0058) and 20 min (p=0.0375) time points. This dose-dependent temporal trend was replicated in eyes with primary nasal pterygium (p=0.31)., Conclusions: The findings suggest that OCTA can reliably and accurately detect and quantify relative changes in the perilimbal vasculature in both normal eyes and in eyes with pterygium., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To analyse the additional clinical value of protocol-driven and selective use of multidetector single-photon-emission tomography/computed tomography (SPECT/CT) in oncology patients undergoing whole-body bone scintigraphy (BS) and to analyse reporter confidence in diagnosis with and without SPECT/CT., Materials and Methods: During a 2-year period, 2,954 whole-body BS examinations were performed in oncology patients, with 444 (15%) undergoing additional protocol-driven SPECT/CT. Retrospective evaluation of planar BS and SPECT/CT images was performed by two experienced dual-trained nuclear medicine radiologists. The BS and SPECT/CT images were graded blindly using a five-point scale designed to evaluate the likelihood of a lesion being benign or malignant. Interpretation was applied on a per-patient basis., Results: There was a 74.5% increase in definitive diagnostic classification and a 26.6% reduction in equivocal findings with SPECT/CT when compared to BS alone (p<0001). Of cases initially classified as "probably benign" on BS, 5.1% (10/193) were reclassified to "probably malignant" (1%) or "malignant" (4.1%) using the SPECT/CT data. The highest impact in reporter confidence was seen with SPECT/CT in the interpretation of lesions within the pelvis (34%), ribs (23%), lumbar spine (22%), and thoracic spine (21%)., Conclusion: Protocol-driven, selective use of SPECT/CT imaging to augment planar BS reduces equivocal findings and improves reporter confidence whilst minimising the impact on patient and reporting workflows., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Synthesis of novel and potent hit molecules has an eternal demand. It is our continuous study to search novel bioactive hit molecules and as a part of this, a series of novel N'-isonicotinoyl-2-methyl-4-(pyridin-2-yl)-4H-benzo[4,5]thiazolo[3,2-a]pyrimidine-3-carbohydrazide analogs (5a-5n) were synthesized with good yields by the conventional method. The various novel compounds have been characterized and identified by many analytical technique such as IR, 1 H NMR, 13 C NMR, mass spectral analysis, and elemental analysis. All the synthetic analogs (5a-5n) are evaluated for their in vitro antibacterial and anti-mycobacterial activities against different bacterial strains. Molecular docking and Molecular dynamics studies were helped in revealing the mode of action of these compounds through their interactions with the active site of the Mycobacterium tuberculosis enoyl reductase (InhA) enzyme. The calculated ADMET descriptors for the synthesized compounds validated good pharmacokinetic properties, confirming that these compounds could be used as templates for the development of new Anti-mycobacterial agents., (Copyright © 2019. Published by Elsevier Masson SAS.)

Simple limbal epithelial transplantation (SLET) is an innovative limbal stem cell transplantation technique that has gained increasing popularity over the last few years. Different groups from across the world have published the clinical results of SLET in large case series with varying types and severities of limbal stem cell deficiency (LSCD). This review attempts to place all the available knowledge on SLET together in one place for the benefit of not only cornea specialists and trainees but also for residents and general ophthalmologists. It follows a balanced approach of blending evidence with experience by providing an objective analysis of published results along with helpful insights from subject experts, starting from preoperative considerations including the role of newer imaging modalities to the technical aspects of the surgery itself and the management of possible complications. Original data and novel insights on allogeneic SLET for bilateral LSCD are included in the review to address the few remaining lacunae in the existing literature on this topic. This review intends to inform, educate, and empower all aspiring and practicing SLET surgeons to optimize their clinical outcomes and to have maximal positive impact on the lives of the individuals affected by unilateral or bilateral chronic LSCD., Competing Interests: There are no conflicts of interest

Cardiotonic steroids (CTS) are steroidal drugs, processed from the seeds and dried leaves of the genus Digitalis as well as from the skin and parotid gland of amphibians. The most commonly known CTS are ouabain, digoxin, digoxigenin and bufalin. CTS can be used for safer medication of congestive heart failure and other related conditions due to promising pharmacological and medicinal properties. Ouabain isolated from plants is widely utilized in in vitro studies to specifically block the sodium potassium (Na + /K + -ATPase) pump. For checking, whether ouabain derivatives are robust inhibitors of Na + /K + -ATPase pump, molecular docking simulation was performed between ouabain and its derivatives using YASARA software. The docking energy falls within the range of 8.470 kcal/mol to 7.234 kcal/mol, in which digoxigenin was found to be the potential ligand with the best docking energy of 8.470 kcal/mol. Furthermore, pharmacophore modeling was applied to decipher the electronic features of CTS. Molecular dynamics simulation was also employed to determine the conformational properties of Na + /K + -ATPase-ouabain and Na + /K + -ATPase-digoxigenin complexes with the plausible structural integrity through conformational ensembles for 100 ns which promoted digoxigenin as the most promising CTS for treating conditions of congestive heart failure patients.

Purpose: Limbal ischemia is an important prognostic factor in the management of ocular burns. In this study, we evaluated the reliability of clinically assessing limbal ischemia among ophthalmic professionals., Methods: This study included 111 ophthalmic professionals who were shown 12 diffuse illumination color slit-lamp photographs of eyes with recent chemical injuries. Respondents were asked whether the photos were assessable and if yes, then to indicate the presence, location, and grade of limbal ischemia in each case. The responses were collected using a standard data collection sheet and the inter-observer agreement was calculated., Results: All participants responded to every question. Of the 1,332 responses, images were deemed assessable in 1,222 (91.7%) instances. The overall agreement (Fleiss' kappa) for the presence of limbal ischemia and severity of limbal ischemia was 0.106 and 0.139, respectively (P < 0.012). Among the four groups of observers, practicing cornea specialists displayed significantly (P < 0.003) higher kappa values (0.201-0.203) when compared to residents (0.131-0.185), fellows (0.086-0.127), and optometrists (0.077-0.102). All indicated a poor level of inter-rater consistency., Conclusion: The results indicate that clinical assessment of limbal ischemia is highly subjective and there is lack of reliability even among cornea specialists who regularly manage patients with ocular burns. A non-invasive, standardized, objective, accurate, and reliable modality for ocular surface angiography is desperately needed for proper assessment and prognostication of ocular burns., Competing Interests: None

Background: Missing doses of antibiotics in hospitalized patients is a well-described but inadequately recognized issue. We hypothesized that missing doses of antibiotics decreases quality of care., Methods: Retrospective study on patients admitted to the Shock Trauma ICU from February to June 2015. Patients prescribed a multidose course of antibiotics were evaluated. A missed antibiotic dose was one ordered but never given (a completely missed dose) or a dose that was not given within an hour before or after the planned time (an off-schedule missed dose). Patient outcomes included a positive culture, ventilator, ICU and hospital length of stay (LOS), and mortality. Multiple statistical methods were used as appropriate; significance was set as P < 0.05., Results: For the 5-mo study period, 280 patients were admitted and 200 met inclusion criteria. Eight percent of patients (16/200) did not miss any antibiotic doses, 39% (77/200) had only off-schedule doses, 2% (4/200) had only completely missed doses, and 51% (103/200) had both off-schedule and completely missed doses. For the 200 patients, 8167 doses were ordered and 2096 (26%) were missed. Adjusting for age, gender, BMI, injury severity score, and doses of antibiotics showed that those who miss doses off-schedule had longer LOS than those who do not miss doses of antibiotics. There was a significant nonlinear relationship between LOS and frequency of early (P-value = 0.02) and late (P-value = 0.01) doses., Conclusions: To reduce length of hospital stay and optimize quality, methods to improve compliance with antibiotic dosing schedules should be investigated., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is one of the most significant neurodegenerative disorders and its symptoms mostly appear in aged people. Catechol-o-methyltransferase (COMT) is one of the known target enzymes responsible for AD. With the use of 23 known inhibitors of COMT, a query has been generated and validated by screening against the database of 1500 decoys to obtain the GH score and enrichment value. The crucial features of the known inhibitors were evaluated by the online ZINC Pharmer to identify new leads from a ZINC database. Five hundred hits were retrieved from ZINC Pharmer and by ADMET (absorption, distribution, metabolism, excretion, and toxicity) filtering by using FAF-Drug-3 and 36 molecules were considered for molecular docking. From the COMT inhibitors, opicapone, fenoldopam, and quercetin were selected, while ZINC63625100&#95;413 ZINC39411941&#95;412, ZINC63234426&#95;254, ZINC63637968&#95;451, and ZINC64019452&#95;303 were chosen for the molecular dynamics simulation analysis having high binding affinity and structural recognition. This study identified the potential COMT inhibitors through pharmacophore-based inhibitor screening leading to a more complete understanding of molecular-level interactions.

Bisphenol A (BPA) is an endocrine disruptor of xenobiotic type, mainly used for the production of polycarbonate plastic, epoxy resins and non-polymer additives. Because of its wide usages in the environment, the toxic effects of BPA have proved to be harmful to human health. However, its effects on human haemoglobin remain unclear. The affinity between BPA and haemoglobin, as well as erythrocytes, is an important factor in understanding the mechanism of the toxicity of BPA. Flavonoids are strong antioxidants that prevent oxidative stress and Quercetin is a flavonoid found in numerous vegetables and fruits. Therefore, the present investigation was undertaken to investigate whether Quercetin can be used to alleviate the toxic effects of BPA in vitro in human red blood cells (RBC). Venous blood samples were collected from healthy, well-nourished adult volunteers (25-30 years old) by phlebotomy. In a RBC suspension with a cell density of 2 × 104 cell per mL, the concentration of BPA (25-150 µg mL -1 ) was found to cause an increase in the lipid peroxidation (LPO) and a decrease in the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) in human RBC. However, the concurrent addition of BPA (150 µg mL -1 ) and quercetin (10-50 µg mL -1 ) lead to significant amelioration. In silico studies gave structural insight into BPA and quercetin to decipher the plausible binding mechanism and molecular level recognition.

In the current investigation, we prepared a series of novel spiro[indole-thiazolidines] derivatives (5a-5h) from 5-substituted isatin derivatives and thioglycolic acid (TGA) with ZrSiO 2 as an efficient catalyst under microwave irradiation. The significant merits of this protocol have some significant merits such as simplicity in operation, simple, efficient workup, good practical yields of product and the employment of recyclable catalyst. All the new synthesized scaffold has been well characterized by various spectroscopic methods and elemental analysis. All the spiro scaffolds were subjected to in vitro anti-mycobacterial activity against the Mycobacterium tuberculosis (H 37 Rv) strain. We have carried out molecular docking study of our synthesized compounds. We also calculated theoretically ADME-Tox parameters for synthesized compounds.

Aim: To assess the feasibility and efficacy of a streamlined single time-point 99m Tc-HYNIC-Tyr3-octreotide (Tektrotyd) somatostatin receptor scintigraphy (SRS) protocol to differentiate pathological uptake by neuroendocrine tumours (NETs) from physiological activity., Methods and Materials: Tektrotyd imaging in 50 consecutive patients with NETs was reviewed retrospectively. Imaging was independently assessed by two experienced reporters with dual-certification in radiology and nuclear medicine and agreed in consensus. The presence of physiological bowel activity and/or further sites of equivocal uptake on 4-hour planar imaging and whether combined single-photon-emission computed tomography (SPECT)/computed tomography (CT) assessment allowed accurate diagnosis was tabulated. A judgement was also made in each case on whether 2-hour planar imaging was necessary for accurate diagnostic interpretation., Results: Thirty-six patients (72%) had positive findings on Tektrotyd SPECT/CT. Eight patients (16%) had bowel activity on 4-hour planar imaging, which could be considered to have hampered interpretation without access to SPECT/CT. Eleven studies in 10 patients (20%) demonstrated areas of indeterminate uptake on planar imaging; five in the uncinate process of the pancreas, three in the nasal cavity or paranasal sinuses, one in the adrenal glands, one in a focus of inflammation on the posterior abdominal wall, and one at the tip of a central venous line. In all cases, accurate interpretation of findings was possible with SPECT/CT, without the 2-hour planar image., Conclusion: Two-hour planar imaging could be safely omitted from Tektrotyd SRS incorporating SPECT/CT imaging without reducing the accuracy of diagnostic interpretation. Streamlined imaging has the potential to reduce patient inconvenience and improve scanner and staff efficiency., (Copyright © 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Stem cells, including neural stem cells (NSCs), are endowed with self-renewal capability and hence hold great opportunity for the institution of replacement/protective therapy. We propose a method for in vitro generation of stromal cells from human adipose tissue and their differentiation into neural cells., Materials and Methods: Ten grams of donor adipose tissue was surgically resected from the abdominal wall of the human donor after the participants' informed consents. The resected adipose tissue was minced and incubated for 1 hour in the presence of an enzyme (collagenase-type I) at 37 0 C followed by its centrifugation. After centrifugation, the supernatant and pellets were separated and cultured in a medium for proliferation at 37 0 C with 5% CO2 for 9-10 days in separate tissue culture dishes for generation of mesenchymal stromal cells (MSC). At the end of the culture, MSC were harvested and analyzed. The harvested MSC were subjected for further culture for their differentiation into neural cells for 5-7 days using differentiation medium mainly comprising of neurobasal medium. At the end of the procedure, culture cells were isolated and studied for expression of transcriptional factor proteins: orthodenticle homolog-2 (OTX-2), beta-III-tubulin (β3-Tubulin), glial-fibrillary acid protein (GFAP) and synaptophysin-β2., Results: In total, 50 neural cells-lines were generated. In vitro generated MSC differentiated neural cells' mean quantum was 5.4 ± 6.9 ml with the mean cell count being, 5.27 ± 2.65 × 10 3/ μl. All of them showed the presence of OTX-2, β3-Tubulin, GFAP, synaptophysin-β2., Conclusion: Neural cells can be differentiated in vitro from MSC safely and effectively. In vitro generated neural cells represent a potential therapy for recovery from spinal cord injuries and neurodegenerative disease., Competing Interests: There are no conflicts of interest

The DNA repair process protects the cells from DNA damaging agent by multiple pathways. Majority of the cancer therapy cause DNA damage which leads to apoptosis. The cell has natural ability to repair this damage which ultimately leads to development of resistance of drugs. The key enzymes involved in DNA repair process are poly(ADP-ribose) (PAR) and poly(ADP-ribose) polymerases (PARP). Tumor cells repair their defective gene via defective homologues recombination (HR) in the presence of enzyme PARP. PARP inhibitors inhibit the enzyme poly(ADP-ribose) polymerases (PARPs) which lead to apoptosis of cancer cells. Current clinical data shows the role of PARP inhibitors is not restricted to BRCA mutations but also effective in HR dysfunctions related tumors. Therefore, investigation in this area could be very helpful for future therapy of cancer. This review gives detail information on the role of PARP in DNA damage repair, the role of PARP inhibitors and chemistry of currently available PARP inhibitors.

The identification of isatin sulfonamide as a potent small molecule inhibitor of caspase-3 had fuelled the synthesis and characterization of the numerous sulfonamide class of inhibitors to optimize for potency. Recent works that relied on the ligand-based approaches have successfully shown the regions of optimizations for sulfonamide scaffold. We present here molecular dynamics-based pharmacophore modeling of caspase-3-isatin sulfonamide crystal structure, to elucidate the essential non-covalent contacts and its associated pharmacophore features necessary to ensure caspase-3 optimal binding. We performed 20ns long dynamics of this crystal structure to extract global conformation states and converted into structure-based pharmacophore hypotheses which were rigorously validated using an exclusive focussed library of experimental actives and inactives of sulfonamide class by Receiver Operating Characteristic (ROC) statistic. Eighteen structure-based pharmacophore hypotheses with better sensitivity and specificity measures (>0.6) were chosen which collectively showed the role of pocket residues viz. Cys163 (S 1 sub-site; required for covalent and H bonding with Michael acceptor of inhibitors), His121 (S 1 ; π stack with bicyclic isatin moiety), Gly122 (S 1 ; H bond with carbonyl oxygen) and Tyr204 (S 2 ; π stack with phenyl group of the isatin sulfonamide molecule) as stringent binding entities for enabling caspase-3 optimal binding. The introduction of spatial pharmacophore site points obtained from dynamics-based pharmacophore models in a virtual screening strategy will be helpful to screen and optimize molecules belonging to sulfonamide class of caspase-3 inhibitors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)