Search results for: small molecule inhibitors

Authors: Francesco Pantano, Marta Fogolari, Michele Iuliani, Sonia Simonetti, Silvia Cavaliere, Marco Russano, Fabrizio Citarella, Bruno Vincenzi, Silvia Angeletti, Giuseppe Tonini

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Background: Although immune checkpoint inhibitors (ICIs) have changed the treatment paradigm of non–small cell lung cancer (NSCLC), these drugs fail to elicit durable responses in the majority of NSCLC patients. The gut microbiota, able to regulate immune responsiveness, is emerging as a promising, modifiable target to improve ICIs response rates. Since the oral microbiome has been demonstrated to be the primary source of bacterial microbiota in the lungs, we investigated its composition as a potential predictive biomarker to identify and select patients who could benefit from immunotherapy. Methods: Thirty-five patients with stage IV squamous and non-squamous cell NSCLC eligible for an anti-PD-1/PD-L1 as monotherapy were enrolled. Saliva samples were collected from patients prior to the start of treatment, bacterial DNA was extracted using the QIAamp® DNA Microbiome Kit (QIAGEN) and the 16S rRNA gene was sequenced on a MiSeq sequencing instrument (Illumina). Results: NSCLC patients were dichotomized as “Responders” (partial or complete response) and “Non-Responders” (progressive disease), after 12 weeks of treatment, based on RECIST criteria. A prevalence of the phylum Candidatus Saccharibacteria was found in the 10 responders compared to non-responders (abundance 5% vs 1% respectively; p-value = 1.46 x 10-7; False Discovery Rate (FDR) = 1.02 x 10-6). Moreover, a higher prevalence of Saccharibacteria Genera Incertae Sedis genus (belonging to the Candidatus Saccharibacteria phylum) was observed in "responders" (p-value = 6.01 x 10-7 and FDR = 2.46 x 10-5). Finally, the patients who benefit from immunotherapy showed a significant abundance of TM7 Phylum Sp Oral Clone FR058 strain, member of Saccharibacteria Genera Incertae Sedis genus (p-value = 6.13 x 10-7 and FDR=7.66 x 10-5). Conclusions: These preliminary results showed a significant association between oral microbiota and ICIs response in NSCLC patients. In particular, the higher prevalence of Candidatus Saccharibacteria phylum and TM7 Phylum Sp Oral Clone FR058 strain in responders suggests their potential immunomodulatory role. The study is still ongoing and updated data will be presented at the congress.

Keywords: oral microbiota, immune checkpoint inhibitors, non-small cell lung cancer, predictive biomarker

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Authors: Aleksandra Twarda, Dobrosława Krzemień, Grzegorz Dubin, Tad A. Holak

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Stabilin-2 belongs to the group of scavenger receptors and plays a crucial role in clearance of more than 10 ligands from the bloodstream, including hyaluronic acid, products of degradation of extracellular matrix and metabolic products. The Link domain, a defining feature of stabilin-2, has a sequence similar to Link domains in other hyaluronic acid receptors, such as CD44 or TSG-6, and is responsible for most of ligands binding. Present knowledge of signal transduction by stabilin-2, as well as ligands’ recognition and binding mechanism, is limited. Until now, no experimental structures have been solved for any segments of stabilin-2. It has recently been demonstrated that the stabilin-2 knock-out or blocking of the receptor by an antibody effectively opposes cancer metastasis by elevating the level of circulating hyaluronic acid. Moreover, loss of expression of stabilin-2 in a peri-tumourous liver correlates with increased survival. Solving of the crystal structure of stabilin-2 and elucidation of the binding mechanism of hyaluronic acid could enable the precise characterization of the interactions in the binding site. These results may allow for designing specific small-molecule inhibitors of stabilin-2 that could be used in cancer therapy. To carry out screening for crystallization of stabilin-2, we cloned constructs of the Link domain of various lengths with or without surrounding domains. The folding properties of the constructs were checked by nuclear magnetic resonance (NMR). It is planned to show the binding of hyaluronic acid to the Link domain using several biochemical methods, i.a. NMR, isothermal titration calorimetry and fluorescence polarization assay.

Keywords: stabilin-2, Link domain, X-ray crystallography, NMR, hyaluronic acid, cancer

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Authors: Ireneusz Majsterek, Dariusz Pytel, J. Alan Diehl

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PKR-like ER kinase (PERK) is serine/threonie endoplasmic reticulum (ER) transmembrane kinase activated during ER-stress. PERK can activate signaling pathways known as unfolded protein response (UPR). Attenuation of translation is mediated by PERK via phosphorylation of eukaryotic initiation factor 2α (eIF2α), which is necessary for translation initiation. PERK activation also directly contributes to activation of Nrf2 which regulates expression of anti-oxidant enzymes. An increased phosphorylation of eIF2α has been reported in Alzheimer disease (AD) patient hippocampus, indicating that PERK is activated in this disease. Recent data have revealed activation of PERK signaling in non-Hodgkins lymphomas. Results also revealed that loss of PERK limits mammary tumor cell growth in vitro and in vivo. Consistent with these observations, activation of UPR in vitro increases levels of the amyloid precursor protein (APP), the peptide from which beta-amyloid plaques (AB) fragments are derived. Finally, proteolytic processing of APP, including the cleavages that produce AB, largely occurs in the ER, and localization coincident with PERK activity. Thus, we expect that PERK-dependent signaling is critical for progression of many types of diseases (human cancer, neurodegenerative disease and other). Therefore, modulation of PERK activity may be a useful therapeutic target in the treatment of different diseases that fail to respond to traditional chemotherapeutic strategies, including Alzheimer’s disease. Our goal will be to developed therapeutic modalities targeting PERK activity.

Keywords: PERK kinase, small molecule inhibitor, neurodegenerative disease, Alzheimer’s disease

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Authors: Filipa Vasconcelos

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The administration of endoplasmic reticulum amino peptidases (ERAP1 or ERAP2) inhibitors can be used for therapeutic approaches against cancer and auto-immune diseases. However, one of the main shortcomings of drug delivery systems (DDS) is associated with the drug off-target distribution, which can lead to an increase in its side effects on the patient’s body. To overcome such limitations, the encapsulation of four representative compounds of ERAP inhibitors into Polycaprolactone (PCL), Polyvinyl-alcohol (PVA), crosslinked PVA, and PVA with nanoparticles (liposomes) electrospun fibrous meshes is proposed as a safe and controlled drug release system. The use of electrospun fibrous meshes as a DDS allows efficient solvent evaporation giving limited time to the encapsulated drug to recrystallize, continuous delivery of the drug while the fibers degrade, prevention of initial burst release (sustained release), tunable dosages, and the encapsulation of other agents. This is possible due to the fibers' small diameters and resemblance to the extracellular matrix (confirmed by scanning electron microscopy results), high specific surface area, and good mechanical strength/stability. Furthermore, release studies conducted on PCL, PVA, crosslinked PVA, and PVA with nanoparticles (liposomes) electrospun fibrous meshes with each of the ERAP compounds encapsulated demonstrated that they were capable of releasing >60%, 50%, 40%, and 45% of the total ERAP concentration, respectively. Fibrous meshes with ERAP_E compound encapsulated achieved higher released concentrations (75.65%, 62.41%, 56.05%, and 65.39%, respectively). Toxicity studies of fibrous meshes with encapsulated compounds are currently being accessed in vitro, as well as pharmacokinetics and dynamics studies. The last step includes the implantation of the drug-loaded fibrous meshes in vivo.

Keywords: drug delivery, electrospinning, ERAP inhibitors, liposomes

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Authors: Manel Boulakoud, Abdelkader Chouaih, Fodil Hamzaoui

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In the present work we are interested in the determination of the Molecular electrostatic potential (MEP) in Z-3N(2-Ethoxyphenyl), 2-N’(2-Ethoxyphenyl) imino thiazolidin-4-one molecule by ab initio and Density Functional Theory (DFT) in the ground state. The MEP is related to the electronic density and is a very useful descriptor in understanding sites for electrophilic attack and nucleophilic reactions as well as hydrogen bonding interactions. First, geometry optimization was carried out using Hartree–Fock (HF) and DFT methods with 6-311G(d,p) basis set. In order to get more information on the molecule, its stability has been analyzed by natural bond orbital (NBO) analysis. Mulliken population analyses have been calculated. Finally, the molecular electrostatic potential (MEP) and HOMO-LUMO energy levels have been performed. The calculated HOMO and LUMO energies show also the charge transfer within the molecule. The energy gap obtained is about 4 eV which explain the stability of the studied compound. The obtained molecular electrostatic potential from the two methods confirms the nature of the electron charge transfer at the molecular shell and locate the electropositive part and the electronegative part in molecular scale of the title compound.

Keywords: DFT, ab initio, HOMO-LUMO, organic compounds

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Authors: L. Bammou, M. Belkhaouda R. Salghi, L. Bazzi, B. Hammouti

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Steel and steel-based alloys of different grades steel are extensively used in numerous applications where acid solutions are widely applied such as industrial acid pickling, industrial acid cleaning and oil-well acidizing. The use of chemical inhibitors is one of the most practical methods for the protection against corrosion in acidic media. Most of the excellent acid inhibitors are organic compounds containing nitrogen, oxygen, phosphorus and sulphur. The use of non-toxic inhibitors called green or eco-friendly environmental inhibitors is one of the solutions possible to prevent the corrosion of the material. These advantages have incited us to draw a large part of program of our laboratory to examine natural substances as corrosion inhibitors such as: prickly pear seed oil, Argan oil, Argan extract, Fennel oil, Rosemary oil, Thymus oil, Lavender oil, Jojoba oil, Pennyroyal Mint oil, and Artemisia. In the present work, we investigate the corrosion inhibition of steel in 1 M HCl by junipers extract using weight loss, potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) methods. The result obtained of junipers extract (JE) shows excellent inhibition properties for the corrosion of C38 steel in 1M HCl at 298K, and the inhibition efficiency increases with increasing of the JE concentration. The inhibitor efficiencies determined by weight loss, Tafel polarisation and EIS methods are in reasonable agreement. Based on the polarisation results, the investigated junipers extract can be classified as mixed inhibitor. The calculated structural parameters show increase of the obtained Rct values and decrease of the capacitance, Cdl, with JE concentration increase. It is suggested to attribute this to the increase of the thickness of the adsorption layer at steel surface. The adsorption model obeys to the Langmuir adsorption isotherm. The adsorption process is a spontaneous and exothermic process.

Keywords: corrosion inhibition, steel, friendly inhibitors, Tafel polarisation

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Authors: Ji-Seok Hong, Hee-Jang Moon, Hong-Gye Sung

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The details of flow structures and the coupling mechanism between vortex shedding and acoustic excitation in a solid rocket motor with two inhibitors have been investigated using 3D Large Eddy Simulation (LES) and Proper Orthogonal Decomposition (POD) analysis. The oscillation frequencies and vortex shedding periods from two inhibitors compare reasonably well with the experimental data and numerical result. A total of four different locations of the rear inhibitor has been numerically tested to characterize the coupling relation of vortex shedding frequency and acoustic mode. The major source of triggering pressure oscillation in the combustor is the resonance with the acoustic longitudinal half mode. It was observed that the counter-rotating vortices in the nozzle flow produce roll torque.

Keywords: large eddy simulation, proper orthogonal decomposition, SRM instability, flow-acoustic coupling

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Authors: Nabila Mohamed, Santiago Aparicio, Bahman Tohidi, Mert Atilhan

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Qatar's one of the biggest problem in processing its natural resource, which is natural gas, is the often occurring blockage in the pipelines caused due to uncontrolled gas hydrate formation in the pipelines. Several millions of dollars are being spent at the process site to dehydrate the blockage safely by using chemical inhibitors. We aim to establish national database, which addresses the physical conditions that promotes Qatari natural gas to form gas hydrates in the pipelines. Moreover, we aim to design and test novel hydrate inhibitors that are suitable for Qatari natural gas and its processing facilities. From these perspectives we are aiming to provide more effective and sustainable reservoir utilization and processing of Qatari natural gas. In this work, we present the initial findings of a QNRF funded project, which deals with the natural gas hydrate formation characteristics of Qatari type gas in both experimental (PVTx) and computational (molecular simulations) methods. We present the data from the two fully automated apparatus: a gas hydrate autoclave and a rocking cell. Hydrate equilibrium curves including growth/dissociation conditions for multi-component systems for several gas mixtures that represent Qatari type natural gas with and without the presence of well known kinetic and thermodynamic hydrate inhibitors. Ionic liquids were designed and used for testing their inhibition performance and their DFT and molecular modeling simulation results were also obtained and compared with the experimental results. Results showed significant performance of ionic liquids with up to 0.5 % in volume with up to 2 to 4 0C inhibition at high pressures.

Keywords: gas hydrates, natural gas, ionic liquids, inhibition, thermodynamic inhibitors, kinetic inhibitors

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Authors: Hemlata Chitte, Anita Chorey, V. M. Bhale, Bharti Tijare

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A field experiment was conducted during kharif season of 2013-14 at Agronomy research farm, Dr. PDKV, Akola, to study the productivity and nitrogen use efficiency in cotton using organic nitrification inhibitors. The experiment was laid out in factorial randomized block design with three replications each having nine treatment combinations comprising three fertilizer levels viz., 75% RDF (F1), 100% RDF (F2) and 125% RDF (F3) and three nitrification inhibitors viz., neem cake @ 300 kgha-1 (N1), karanj cake @ 300 kgha-1 (N2) and control (N3). The result showed that various growth attributes viz., plant height, number of functional leaves plant-1, monopodial and sympodial branches and leaf area plant-1(dm2) were maximum in fertilizer level 125% RDF over fertilizer level 75% RDF and which at par with 100% RDF. In case of yield attributes and yield, number of bolls per plant, Seed cotton yield and stalk yield kg ha-1 significantly higher in fertilizer level 125% RDF over 100% RDF and 75% RDF. Uptake of NPK kg ha-1 after harvest of cotton crop was significantly higher in fertilizer level 125% RDF over 100% RDF and 75% RDF. Significantly highest nitrogen use efficiency was recorded with fertilizer level 75 % RDF as compared to 100 % RDF and lowest nitrogen use efficiency was recorded with 125% RDF level. Amongst nitrification inhibitors, karanj cake @ 300 kg ha-1 increases potentiality of growth characters, yield attributes, uptake of NPK and NUE as compared to control and at par with neem cake @ 300 kgha-1. Interaction effect between fertilizer level and nitrification inhibitors were found to be non significant at all growth attributes and uptake of nutrient but was significant in respect of seed cotton yield.

Keywords: cotton, fertilizer level, nitrification inhibitor and nitrogen use efficiency, nutrient uptake

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Authors: Fatiha Benghanem, Mokhtar Berarma, Saida Keraghel, Ali Ourari

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Corrosion is the result of the reaction between a material and its environment. Steel in concrete is protected from corrosion by a passive film promoted by concrete alkalinity. For the initiation of corrosion, this protective film must be destroyed and this can be mainly done in two ways: by the attack of chlorides on the steel or by carbonation of the cover concrete due the reaction with carbon dioxide, which causes reduction in the alkalinity of concrete. The literature reports several ways to decrease or to prevent reinforcement corrosion. Among them, the use of corrosion inhibitors has been an envisaged solution. Two approaches are generally used to evaluate the efficiency of inhibitors for concrete application; one uses simulated pore solution testing , and the other uses actual concrete or mortar specimens. Both methods are some times used in conjunction. The aim of this study is to investigate the use of 2,3-diaminopyridine as a corrosion inhibitors of steel in alkaline media which simulate the electrolyte in the concrete pores. The effectiveness of this compound as corrosion inhibitor was investigated by measuring the corrosion potentials, the polarization curves and the corrosion current densities of steel with and without chlorides. The study of corrosion inhibition by this compound led to the conclusion that he has low rates of inhibition in the absence of aggressive ions and high rates in their presence. This type of organic compounds are promoting for the protection of armatures in concrete.

Keywords: corrosion, inhibitors, mild steel, conjunction

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Authors: Son Nguyen, Thanh Van, Ly Le

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Ca2+ - dependent calmodulin kinase IIa (CaMKIIa) has recently been found to associate with protein tau missorting and polymerization in Alzheimer’s Disease (AD). However, there has yet inhibitors targeting CaMKIIa to investigate the correlation between CaMKIIa activity and protein tau polymer formation. Combining virtual screening and our statistics in binding contribution scoring function (BCSF), we rationally identified potential compounds that bind to specific CaMKIIa active site and specificity-affinity distribution of the ligand within the active site. Using molecular dynamics simulation, we identified structural stability of CaMKIIa and potent inhibitors, and site-directed bonding, separating non-specific and specific molecular interaction features. Despite of variation in confirmation of simulation time, interactions of the potent inhibitors were found to be strongly associated with the unique chemical features extracted from molecular binding poses. In addition, competitive inhibitors within CaMKIIa showed an important molecular recognition pattern toward specific ligand features. Our approach combining virtual screening with BCSF may provide an universally applicable method for precise identification in the discovery of compounds.

Keywords: Alzheimer’s disease, Ca 2+ -dependent calmodulin kinase IIa, protein tau, molecular docking

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Authors: J. Iqbal, Z. Zara

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Five new Acceptor-Donor-Acceptor (A-D-A) type small donor molecules (M1-M5) namely; dimethyl cyanoacetate terthiophene di(methylthiophene) dibenzosilole (DMCAO3TBS) (M1), dimelononitrile terthiophene di(methylthiophene) dibenzosilole (DMCNTBS) (M2), dimethyl rhodanine terthiophene di(methylthiophene) dibenzosilole (DMRTBS) (M3), dimelanonitrile terthiophene di(methylthiophene) methyl fluorene (DMCNTF) (M4) and dimethyl rhodanine terthiophene di(methylthiophene) methyl fluorine (DMRTF) (M5) were designed and theoretically explored their electronic, photophysical and geometrical properties via DFT best functional MPW1PW91/6-311G (d,p) level of theory with respect to reference molecules dioctyl cyanoacetate terthiophene di(octylthiophene) dioctylfluorene (DCAO3TF) (Ra) and dioctyl cyanoacetate terthiophene di(octylthiophene) octylcarbazole (DCAO3TCz) (Rb). Among the designed donor molecules (M1-M5), M2 and M4 represented lowest band gap value (2.480 eV and 2.47 eV) with distinctive broad absorption peak at 598 and 601 nm in chloroform due to the presence of stronger electron withdrawing acceptor molecule which pulls the λmax value towards red shift. Theoretically estimated reorganization energies of these molecules recommended excellent property of charge mobility. The designed donor molecules M1-M5, demonstrated lower λe value with reference to their λh, showing that these molecules could be ideal candidates for the transfer of electron with and M2, M4 are best among these as champion molecules with having lowest λe (0.006 D and 0.005 D respectively). Additionally, the Voc of M2 and M4 are 2.01 eV and 1.85 eV respectively with reference respect to PCBM. Thus, our present investigation suggested that our designed donor molecules (M1-M5) are suitable candidates for the solar cell and proposed for high and better performance for the small molecule based solar cell devices.

Keywords: dibenzisilol, donor materials, hole mobility, organic solar cells

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Authors: Mouna Baassi, Mohamed Moussaoui, Hatim Soufi, Sanchaita RajkhowaI, Ashwani Sharma, Subrata Sinha, Said Belaaouad

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Human Immunodeficiency Virus type 1 protease (HIV-1 PR) is one of the most challenging targets of antiretroviral therapy used in the treatment of AIDS-infected people. The performance of protease inhibitors (PIs) is limited by the development of protease mutations that can promote resistance to the treatment. The current study was carried out using statistics and bioinformatics tools. A series of thirty-three compounds with known enzymatic inhibitory activities against HIV-1 protease was used in this paper to build a mathematical model relating the structure to the biological activity. These compounds were designed by software; their descriptors were computed using various tools, such as Gaussian, Chem3D, ChemSketch and MarvinSketch. Computational methods generated the best model based on its statistical parameters. The model’s applicability domain (AD) was elaborated. Furthermore, one compound has been proposed as efficient against HIV-1 protease with comparable biological activity to the existing ones; this drug candidate was evaluated using ADMET properties and Lipinski’s rule. Molecular Docking performed on Wild Type and Mutant Type HIV-1 proteases allowed the investigation of the interaction types displayed between the proteases and the ligands, Darunavir (DRV) and the new drug (ND). Molecular dynamics simulation was also used in order to investigate the complexes’ stability, allowing a comparative study of the performance of both ligands (DRV & ND). Our study suggested that the new molecule showed comparable results to that of Darunavir and may be used for further experimental studies. Our study may also be used as a pipeline to search and design new potential inhibitors of HIV-1 proteases.

Keywords: QSAR, ADMET properties, molecular docking, molecular dynamics simulation.

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Authors: Raad Nari, Maura Moriaty, Maha T. Barakat

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Introduction: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a new class of oral anti-diabetic drugs with a unique mechanism of action. They are used to improve glycaemic control in adults with type 2 diabetes by enhancing urinary glucose excretion. In the UAE, there has been certainly an increased use of these medications. As with any new medication, there are safety considerations related to their use in patients with type two diabetes. A retrospective study was conducted at the three main centres of the Imperial College London Diabetes Centre. Methodology: All patients in electronic database (Diamond) from October 2014 to October 2017 were included with a minimum of six months usage of sodium glucose co-transporter inhibitors that comprise canagliflozin, dapagliflozin and empagliflozin. There were 15 paired sample biochemical and clinical correlations. The analysis was done at the start of the study, three months and six months apart. SPSS version 24 was used for this study. Conclusion: This study of sodium glucose co-transporter-2 inhibitors used showed significant reductions in weight, glycated haemoglobin A1C, systolic and diastolic blood pressures. As the case with systematic reviews, there were similar changes in liver enzymes, raised total cholesterol, low density lipopoptein and high density lipoprotein. There was slight improvement in estimated glomerular filtration rate too. Our analysis also showed that they increased in the incidence of urinary tract symptoms and incidence of urinary tract infections.

Keywords: SGLT2 inhibitors dapagliflozin empagliflozin canagliflozin, adverse effects, amputation diabetic ketoacidosis DKA, urinary tract infection

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Authors: Vishnu Varthan Vaithiyalingam Jagannathan, Lakshmi Karunanidhi Santhanalakshmi, Srividya Ammayappan Rajam

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Formononetin is the O-Methoxy Flavonol that has many pharmacological activities, which belongs to the flavonoid family. In the current study, activity of this molecule was evaluated in lung cancer cell lines. In general, flavonoids possess certain anticancer mechanism. Being a flavonoid subfamily, this molecule was subjected to evaluate cytotoxicity assay by MTT ((3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide)) stain, mode of cell death assay stained by acridine orange and ethidium bromide and Evaluation of Apoptosis pathway (extrinsic or intrinsic) by Caspase 3/7 stain and Rhodamine-123 stain. From the results, we could able to confirm that the investigatory molecule formononetin has anticancer activity and in future, the study will propose to evaluate the formononetin action against genetic changes occurs during lung cancer progression.

Keywords: Caspase 3/7, formononetin, lung cancer, Rhodamine-123

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Authors: Ouardi Okkacha, Kaarour Abedlkrim, Meskine Mohamed

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The effective Hamiltonians are widely used in molecular spectroscopy for the interpretation of the vibration-rotation spectra. Their construction is an ambiguous procedure due to the existence of unitary transformations that change the effective Hamiltonian but do not change its eigenvalues. As a consequence of this ambiguity, it may happen that some parameters of effective Hamiltonians cannot be recovered from experimental data in a unique way. The type of admissible transformations which keeps the operator form of the effective Hamiltonian unaltered and the number of empirically determinable parameters strongly depend on the symmetry type of a molecule (asymmetric top, spherical top, and so on) and on the degeneracy of the vibrational state. In this work, we report the study of the ambiguity of effective Hamiltonian for the fundamental degenerate states v3 of the Molecule 12CD4.

Keywords: 12CD4, high-resolution infrared spectra, tetrahedral tensorial formalism, vibrational states, rovibrational line position analysis, XTDS, SPVIEW

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Authors: Rafayel Azizyan, Valeri Arakelyan, Aram Gevorgyan, Varduhi Balayan, Emil Gevorgyan

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Currently, mathematical and computer modeling are widely used in different biological studies to predict or assess behavior of such complex systems as biological ones. This study deals with mathematical and computer modeling of bi-substrate enzymatic reactions, which play an important role in different biochemical pathways. The main objective of this study is to represent the results from in silico investigation of bi-substrate enzymatic reactions in the presence of uncompetitive inhibitors, as well as to describe in details the inhibition effects. Four models of uncompetitive inhibition were designed using different software packages. Particularly, uncompetitive inhibitor to the first [ES1] and the second ([ES1S2]; [FS2]) enzyme-substrate complexes have been studied. The simulation, using the same kinetic parameters for all models allowed investigating the behavior of reactions as well as determined some interesting aspects concerning influence of different cases of uncompetitive inhibition. Besides that shown, that uncompetitive inhibitors exhibit specific selectivity depending on mechanism of bi-substrate enzymatic reaction.

Keywords: mathematical modeling, bi-substrate enzymatic reactions, reversible inhibition

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Authors: Prasanthi Malapati, R. Reshma, Vijay Soni, Perumal Yogeeswari, Dharmarajan Sriram

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In the present study, we attempted to develop Mycobacterium tuberculosis (Mtb) inhibitors by exploring the pharmaceutically underexploited enzyme targets which are majorly involved in cell wall biosynthesis of mycobacteria. For this purpose, glutamate racemase (coded by MurI gene) was selected. This enzyme racemize L-glutamate to D-glutamate required for the construction of peptidoglycan in the bacterial cell wall synthesis process. Furthermore this enzyme is neither expressed nor its product, D-glutamate is normally found in mammals, and hence designing inhibitors against this enzyme will not affect the host system as well act as potential antitubercular drugs. A library of BITS in house compounds were screened against Mtb MurI enzyme. Based on docking score, interactions and synthetic feasibility one hit lead was identified. Further optimization of lead was attempted and its derivatives were synthesized. Forty eight derivatives of 2-phenylbenzo[d]oxazole and 2-phenylbenzo[d]thiazole were synthesized and evaluated for Mtb MurI inhibition study, in vitro activities against Mtb, cytotoxicity against RAW 264.7 cell line. Chemical derivatization of the lead resulted in compounds NR-1213 AND NR-1124 as the potent M. tuberculosis glutamate racemase inhibitors with IC50 of 4-5µM which are remarkable and were found to be non-cytotoxic. Molecular dynamics, dormant models and cardiotoxicity studies of the most active molecules are in process.

Keywords: cell wall biosynthesis, dormancy, glutamate racemase, tuberculosis

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Authors: M. A. Lahmer, K. Guergouri

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In this work, Kinetic Monte Carlo (KMC) method was applied to study the thermal stability of hydrogen in ZnO bulk and thin films. Our simulation includes different possible events such as interstitial hydrogen (Hi) jumps, substitutional hydrogen (HO) formation and dissociation, oxygen and zinc vacancies jumps, hydrogen-VZn complexes formation and dissociation, HO-Hi complex formation and hydrogen molecule (H2) formation and dissociation. The obtained results show that the hidden hydrogen formed during thermal annealing or at room temperature is constituted of both hydrogen molecule and substitutional hydrogen. The ratio of this constituants depends on the initial defects concentration as well as the annealing temperature. For annealing temperature below 300°C hidden hydrogen was found to be constituted from both substitutional hydrogen and hydrogen molecule, however, for higher temperature it is composed essentially from HO defects only because H2 was found to be unstable. In the other side, our results show that the remaining hydrogen amount in sample during thermal annealing depend greatly on the oxygen vacancies in the material. H2 molecule was found to be stable for thermal annealing up to 200°C, VZnHn complexes are stable up to 350°C and HO was found to be stable up to 450°C.

Keywords: ZnO, hydrogen, thermal annealing, kinetic Monte Carlo

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Authors: R. Hosny, Mahmoud F. Mubarak, Heba M. Salem, Asmaa A. Abdelrahman

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Oilfield scaling is a major problem in the oil and gas industry. Scale issues cost the industry millions of dollars in damage and lost production every year. One of the main causes of global production decline is scale. In this study, solid scale inhibitors based on silver tungstate loaded KIT-6 were synthesized and evaluated in both static and scale inhibition modeling. The silver tungstate loaded KIT-6 catalysts were synthesized via a simple impregnated method using 3D mesoporous KIT-6 as support. The synthesized materials were characterized using wide and low XRD, N2 adsorption–desorption analysis, TGA analysis, and FTIR, SEM, and XPS analysis. The scale inhibition efficiency of the synthesized materials was evaluated using a static scale inhibition test. The results of this study demonstrate the potential application of silver tungstate-loaded KIT-6 solid scale inhibitors for the oil and gas industry. The results of this study will contribute to the development of new and innovative solid scale inhibitors based on silver tungstate-loaded KIT-6. The inhibition efficiency of the scale inhibitor increases, and calcite scale inhibitor decreases with increasing pH (2 to8), it proposes that the scale inhibitor was more effective under alkaline conditions. An inhibition efficiency of 99% on calcium carbonate can be achieved at the optimal dosage of 7.5 ppm at 55oC, indicating that the scale inhibitor exhibits a relatively good inhibition performance on calcium carbonate. The use of these materials can potentially lead to more efficient and cost-effective solutions for scaling inhibition in various industrial processes.

Keywords: produced water treatment, solid scale inhibitors, calcite, silver tungestate, 3 D mesoporous KIT-6, oilfield scales, adsorption

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Authors: Xiaolin Li, Terence Turney, John Forsythe, Bryce Feltis, Paul Wright, Vinh Truong, Will Gates

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Clay-hydrogel nanocomposites have attracted great attention recently, mainly because of their enhanced mechanical properties and ease of fabrication. Moreover, the unique platelet structure of clay nanoparticles enables the incorporation of bioactive molecules, such as proteins or drugs, through ion exchange, adsorption or intercalation. This study seeks to improve the mechanical and rheological properties of a novel hydrogel system, copolymerized from a tetrapodal polyethylene glycol (PEG) thiol and a linear, triblock PEG-PPG-PEG (PPG: polypropylene glycol) α,ω-bispropynoate polymer, with the simultaneous incorporation of various amounts of Na-saturated, montmorillonite clay (MMT) platelets (av. lateral dimension = 200 nm), to form a bioactive three-dimensional network. Although the parent hydrogel has controlled swelling ability and its PEG groups have good affinity for the clay platelets, it suffers from poor mechanical stability and is currently unsuitable for potential applications. Nanocomposite hydrogels containing 4wt% MMT showed a twelve-fold enhancement in compressive strength, reaching 0.75MPa, and also a three-fold acceleration in gelation time, when compared with the parent hydrogel. Interestingly, clay nanoplatelet incorporation into the hydrogel slowed down the rate of its dehydration in air. Preliminary results showed that protein binding by the MMT varied with the nature of the protein, as horseradish peroxidase (HRP) was more strongly bound than bovine serum albumin. The HRP was no longer active when bound, presumably as a result of extensive structural refolding. Further work is being undertaken to assess protein binding behaviour within the nanocomposite hydrogel for potential diabetic wound healing applications.

Keywords: hydrogel, nanocomposite, small molecule, wound healing

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Authors: Geetakshi Arora, Danish Malhotra

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Diabetic wounds are serious health issues and often fail to heal, leading to limb amputation that makes the life of the patient miserable. Delayed wound healing has been characterized by an increase in matrix metalloproteinase-9 (MMP-9). Thus research throughout the world has been going on to develop selective MMP-9 inhibitors for aiding diabetic wound healing. Bioactive constituents from natural sources always served as potential leads in drug development with high rates of success. Considering the need for novel selective MMP-9 inhibitors and the importance of natural bioactive compounds in drug development, we have screened a library of bioactive constituents from plant sources that were effective in diabetic wound healing on human MMP-9 (hMMP-9) using molecular docking studies. Screened constituents are ranked according to their dock score, ∆G value (binding affinity), and Ligand efficiency evaluated from FleXX docking and Hyde scoring modules available with drug designing platform LeadIT. Rhamnocitrin showed the highest correlation between dock score, ∆G value (binding affinity), and Ligand efficiency was further explored for binding interactions with hMMP-9. The overall study suggest that Rhamnocitrin is sufficiently decorated with both hydrophilic and hydrophobic substitutions that perfectly block hMMP-9 and act as a potential lead in the design and development of selective hMMP-9 inhibitors.

Keywords: MMP-9, diabetic wound, molecular docking, phytoconstituents

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Authors: Deepika Bhaskar, Neena Wadehra, Megha Gulati, Aruna Narula, R. Vishnu, Gunjan Katyal

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With drug resistance becoming widespread in Plasmodium falciparum infections, development of the alternative drugs is the desired strategy for prevention and cure of malaria. Three drug targets were selected to screen promising drug molecules from the GSK library of around 14000 molecules. Using an in silico structure-based drug designing approach, the differences in binding energies of the substrate and inhibitor were exploited between target sites of parasite and human to design a drug molecule against Plasmodium. The docking studies have shown several promising molecules from GSK library with more effective binding as compared to the already known inhibitors for the drug targets. Though stronger interaction has been shown by several molecules as compare to reference, few molecules have shown the potential as drug candidates though in vitro studies are required to validate the results.

Keywords: plasmodium, malaria, drug targets, in silico studies

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Authors: Shuyi Wu, Chuang Li, Quanshui Zheng, Luping Xu

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Stretching and snipping DNA molecule by microfluidic has important application value in gene analysis by lab on a chip. Movement, deformation and fragmenting of DNA in microfluidic are typical fluid-solid coupling problems. An efficient and common simulation system for researching the movement, deformation and fragmenting of DNA by microfluidic has not been well developed. In our study, Brownian dynamics-finite element method (BD-FEM) is used to simulate the dynamic process of stretching and fragmenting DNA by contraction flow. The shape and parameters of micro-channels are changed to optimize the stretching and fragmenting properties of DNA. Our results indicate that strain rate, resulting from contraction microchannel, is the main control parameter for stretching and fragmenting DNA. There is good consistency between the simulation data and previous experimental result about the single DNA molecule behavior and averaged fragmenting properties in this study. BD-FEM method is an efficient calculating tool to research stretching and fragmenting behavior of single DNA molecule and optimize microfluidic devices for manipulating, stretching and fragmenting DNA.

Keywords: fragmenting, DNA, microfluidic, optimize.

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Authors: Chien Y. Lin, Jung Y. Huang, Leu-Wei Lo

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A growing body of data reveals that the membrane cholesterol molecules can alter the signaling pathways of living cells. However, the understanding about how membrane cholesterol modulates receptor proteins is still lacking. Single-molecule tracking can effectively probe into the microscopic environments and thermal fluctuations of receptor proteins in a living cell. In this study we applies single-molecule optical tracking on ligand-induced dimerization process of EGFRs in the plasma membranes of two cancer cell lines (HeLa and A431) and one normal endothelial cell line (MCF12A). We tracked individual EGFR and dual receptors, diffusing in a correlated manner in the plasma membranes of live cells. We developed an energetic model by integrating the generalized Langevin equation with the Cahn-Hilliard equation to help extracting important information from single-molecule trajectories. From the study, we discovered that ligand-bound EGFRs move from non-raft areas into lipid raft domains. This ligand-induced motion is a common behavior in both cancer and normal cells. By manipulating the total amount of membrane cholesterol with methyl-β-cyclodextrin and the local concentration of membrane cholesterol with nystatin, we further found that the amount of cholesterol can affect the stability of EGFR dimers. The EGFR dimers in the plasma membrane of normal cells are more sensitive to the local concentration changes of cholesterol than EGFR dimers in the cancer cells. Our method successfully captures dynamic interactions of receptors at the single-molecule level and provides insight into the functional architecture of both the diffusing EGFR molecules and their local cellular environment.

Keywords: membrane proteins, single-molecule tracking, Cahn-Hilliard equation, EGFR dimers

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Authors: Iman Adnan Annon, Kadhim F. Alsultan

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This study investigate the internal corrosion of low carbon steel pipelines in the crude oil, as well as prepare and use natural and locally available plant as a natural corrosion inhibiter, the nature extraction achieved by two types of solvents in order to show the solvent effect on inhibition process, the first being distilled water and the second is diethyl ether. FT-IR spectra and using a chemical reagents achieved to detection the presence of many active groups and the presence of tannins, phenols, and alkaloids in the natural extraction. Some experiments were achieved to estimate the performance of a new inhibitor, one of these tests include corrosion measurement by simple immersion in crude oil within and without inhibitors which added in different amounts 30,40,50and 60 ppm at tow temperature 300 and 323k, where the best inhibition efficiencies which get when added the inhibitors in a critical amounts or closest to it, since for the aqueous extract (EB-A) the inhibition efficiency reached (94.4) and (86.71)% at 300 and 323k respectively, and for diethyl ether extract (EB-D) reached (82.87) and (84.6)% at 300 and 323k respectively. Optical microscopy examination have been conducted to evaluate the corrosion nature where it show a clear difference in the topography of the immersed samples surface after add the inhibitors at two temperatures. The results show that the new corrosion inhibitor is not only equivalent to a chemical inhibitor but has greatly improvement properties such as: high efficiency, low cost, non-toxic, easily to produce, and nonpolluting as compared with chemical inhibitor.

Keywords: corrosion in pipeline, inhibitors, crude oil, carbon steel, types of solvent

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Authors: Gomti Devi

Abstract:

Photoisomerization has been attracting to researchers due to its wide range of applications in optical switches, polymeric chains, liquid-crystalline systems and bilayer membranes etc. Azobenzene is a photochromic molecule which exhibits a reversible isomerisation process between its trans and cis isomers of different stability. An investigation has been conducted of the effects of temperature on intensity and position of Raman band of N=N, C-N stretching modes of Azobenzene (AZBN). It was found that the N=N stretching mode of Raman band shape shifts to lower frequency region with the increase in temperature. The Raman intensity was also decreased with the increase of temperature. The change in bandwidth with the increase in temperature has been studied. The FTIR spectrum of the molecule is recorded so as to complement the Raman spectra. In order to investigate the possibility of undergoing dimerization and trimerization as well as the stability of this molecule, ab initio calculation for geometry optimization and vibrational wavenumber calculation have been performed. Theoretically calculated values are found in good agreement with the experimental results.

Keywords: azobenzene, temperature, ab-initio, frequency

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Authors: Birendra Kumar Bista, Rhitik Bista, Prafulla Koirala, Lokendra Mandal, Nikrsh Raj Shrestha, Vivek Kattel

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Introduction: Poorly controlled diabetes is associated with cause and poor outcome of stroke. High blood sugar reduces cerebral blood flow, increases intracranial pressure, cerebral edema and neuronal death, especially among patients with poorly controlled diabetes.1 SGLT2 inhibitors are associated with 50% reduction in hemorrhagic stroke compared with placebo. SGLT2 inhibitors decrease cardiovascular events via reducing glucose, blood pressure, weight, arteriosclerosis, albuminuria and reduction of atrial fibrillation.2,3 No study has been documented in low income countries to see the role of post stroke SGLT2 inhibitors on diabetic patients at and after ICU admission. Aims: The aim of the study was to measure the 12 months outcome of diabetic patients with acute stroke admitted in ICU set up with naïve SGLT2 inhibitors add on therapy. Method: It was prospective cohort study carried out in a 250 bedded tertiary neurology care hospital at the province capital Biratnagar Nepal. Diabetic patient with acute stroke admitted in ICU from 1st January 2022 to 31st December 2022 who were not under SGLT2 inhibitors were included in the study. These patients were managed as per hospital protocol. Empagliflozin was added to the alternate enrolled patients. Empagliflozin was continued at the time of discharged and during follow up unless contraindicated. These patients were followed up for 12 months. Outcome measured were mortality, morbidity requiring readmission or hospital visit other than regular follow up, SGLT2 inhibitors related adverse events, neuropsychiatry comorbidity, functional status and biochemical parameters. Ethical permission was taken from hospital administration and ethical board. Results: Among 147 diabetic cases 68 were not treated with empagliflozin whereas 67 cases were started the SGLT2 inhibitors. HbA1c level and one year mortality was significantly low among patients on empaglifozin arm. Over a period of 12 months 427 acute stroke patients were admitted in the ICU. Out of them 44% were female, 61% hypertensive, 34% diabetic, 57% dyslipidemia, 26% smoker and with median age of 45 years. Among 427 cases 4% required neurosurgical interventions and 76% had hemorrhagic CVA. The most common reason for ICU admission was GCS<8 (51%). The median ICU stay was 5 days. ICU mortality was 21% whereas 1 year mortality was 41% with most common reason being pneumonia. Empaglifozin related adverse effect was seen in 11% most commonly lower urinary tract infection in 6%. Conclusion: Empagliflozin can safely be started among acute stroke with better Hba1C control and low mortality outcome compared to treatment without SGLT2 inhibitor.

Keywords: diabetes, ICU, mortality, SGLT2 inhibitors, stroke

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Authors: Mohammad Faheem, M. Tabish Rehman, Mohd Danishuddin, Asad U. Khan

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The worldwide dissemination of CTX-M type β-lactamases is a threat to human health. Previously, we have reported the spread of blaCTX-M-15 gene in different clinical strains of Enterobacteriaceae from the hospital settings of Aligarh in north India. In view of the varying resistance pattern against cephalosporins and other β-lactam antibiotics, we intended to understand the correlation between MICs and catalytic activity of CTX-M-15. In this study, steady-state kinetic parameters and MICs were determined on E. coli DH5α transformed with blaCTX-M-15 gene that was cloned from Enterobacter cloacae (EC-15) strain of clinical background. The effect of conventional β-lactamase inhibitors (clavulanic acid, sulbactam and tazobactam) on CTX-M-15 was also studied. We have found that tazobactam is the best among these inhibitors against CTX-M-15. The inhibition characteristic of tazobactam is defined by its very low IC50 value (6 nM), high affinity (Ki = 0.017 µM) and better acylation efficiency (k+2/K9 = 0.44 µM-1s-1). It forms an acyl-enzyme covalent complex, which is quite stable (k+3 = 0.0057 s-1). Since increasing resistance has been reported against conventional b-lactam antibiotic-inhibitor combinations, we aspire to design a non-b-lactam core containing b-lactamase inhibitor. For this, we screened ZINC database and performed molecular docking to identify a potential non-β-lactam based inhibitor (ZINC03787097). The MICs of cephalosporin antibiotics in combination with this inhibitor gave promising results. Steady-state kinetics and molecular docking studies showed that ZINC03787097 is a reversible inhibitor which binds non-covalently to the active site of the enzyme through hydrogen bonds and hydrophobic interactions. Though, it’s IC50 (180 nM) is much higher than tazobactam, it has good affinity for CTX-M-15 (Ki = 0.388 µM). This study concludes that ZINC03787097 compound can be used as seed molecule to design more efficient non-b-lactam containing b-lactamase inhibitor that could evade pre-existing bacterial resistance mechanisms.

Keywords: ESBL, non-b-lactam-b-lactamase inhibitor, bioinformatics, biomedicine

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Authors: Tokuei Sako, Paul-Antoine Hervieux

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The energy-level structure of a pair of electron and positron confined in a quasi-one-dimensional nano-scale potential well has been investigated focusing on its trend in the small limit of confinement strength ω, namely, the Wigner molecular regime. An anisotropic Gaussian-type basis functions supplemented by high angular momentum functions as large as l = 19 has been used to obtain reliable full configuration interaction (FCI) wave functions. The resultant energy spectrum shows a band structure characterized by ω for the large ω regime whereas for the small ω regime it shows an energy-level pattern dominated by excitation into the in-phase motion of the two particles. The observed trend has been rationalized on the basis of the nodal patterns of the FCI wave functions.

Keywords: confined systems, positron, wave function, Wigner molecule, quantum dots

Procedia PDF Downloads 390