Search results for: binding constant

Authors: Jay Ananth

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The drug discovery process currently requires numerous years of clinical testing as well as money just for a single drug to earn FDA approval. For drugs that even make it this far in the process, there is a very slim chance of receiving FDA approval, resulting in detrimental hurdles to drug accessibility. To minimize these inefficiencies, numerous studies have implemented computational methods, although few computational investigations have focused on a crucial feature of drugs: lipophilicity. Lipophilicity is a physical attribute of a compound that measures its solubility in lipids and is a determinant of drug efficacy. This project leverages Artificial Intelligence to predict the impact of a drug’s lipophilicity on its performance by accounting for factors such as binding affinity and toxicity. The model predicted lipophilicity and binding affinity in the validation set with very high R² scores of 0.921 and 0.788, respectively, while also being applicable to a variety of target receptors. The results expressed a strong positive correlation between lipophilicity and both binding affinity and toxicity. The model helps in both drug development and discovery, providing every pharmaceutical company with recommended lipophilicity levels for drug candidates as well as a rapid assessment of early-stage drugs prior to any testing, eliminating significant amounts of time and resources currently restricting drug accessibility.

Keywords: drug discovery, lipophilicity, ligand-receptor interactions, machine learning, drug development

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Authors: Peter U. Eze, P. Udaya, Robin J. Evans

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Data hiding can be achieved by Steganography or invisible digital watermarking. For digital watermarking, both accurate retrieval of the embedded watermark and the integrity of the cover image are important. Medical image security in Teleradiology is one of the applications where the embedded patient record needs to be extracted with accuracy as well as the medical image integrity verified. In this research paper, the Constant Correlation Spread Spectrum digital watermarking for medical image tamper detection and accurate embedded watermark retrieval is introduced. In the proposed method, a watermark bit from a patient record is spread in a medical image sub-block such that the correlation of all watermarked sub-blocks with a spreading code, W, would have a constant value, p. The constant correlation p, spreading code, W and the size of the sub-blocks constitute the secret key. Tamper detection is achieved by flagging any sub-block whose correlation value deviates by more than a small value, ℇ, from p. The major features of our new scheme include: (1) Improving watermark detection accuracy for high-pixel depth medical images by reducing the Bit Error Rate (BER) to Zero and (2) block-level tamper detection in a single computational process with simultaneous watermark detection, thereby increasing utility with the same computational cost.

Keywords: Constant Correlation, Medical Image, Spread Spectrum, Tamper Detection, Watermarking

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Authors: Stephen Eyije Abechi, Casimir Emmanuel Gimba, Zaharaddeen Nasiru Garba, Sani Shamsudeen, David Ebuka Authur

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Corrosion inhibition of mild steel in acid medium using Acalypha chamaedrifolia leaves extract as potential green inhibitor was investigated. Gravimetric (weight loss) technique was used for the corrosion studies. Mild steel coupons of 2cm × 1cm × 0.27 cm dimensions were exposed for varying durations of between 24 to 120 hours, in 1M HCl medium containing a varying concentrations of the leaves extract (0.25g/L, - 1.25g/L). The results show that corrosion rates dropped from a value of 0.49 mgcm-2hr-1 for the uninhibited medium to a value of 0.15 mgcm-2hr-1 for the inhibited medium of 1M HCl in 0.25 g/l of the extract. Values of corrosion inhibition efficiencies of 70.38-85.11% were observed as the concentration of the inhibitor were increased from 0.25g/L, - 1.25g/L. Corrosion Inhibition was found to increase with increase in immersion time and temperature. The magnitude of the Ea indicates that the interaction between the metal surface and the inhibitor was chemisorptions. The Adsorption process fit into the Langmuir isotherm model with a correlation coefficient of 0.97. Evidence from molecular dynamics model shows that Methyl stearate (Line 5) and (3Z, 13Z)-2-methyloctadeca-3,13-dien-1-ol (line 11) were found to have the highest binding energy of -197.69 ± 3.12 and-194.56 ± 10.04 in kcal/mol respectively. The binding energy of these compounds indicates that they would be a very good corrosion inhibitor for mild steel and other Fe related materials.

Keywords: binding energy, corrosion, inhibitor, langmuir isotherm, mild steel

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Authors: Nikhil Agrawal, Adam A. Skelton

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Alzheimer’s disease (AD) is one of the most common forms of dementia, which is caused by misfolding and aggregation of amyloid beta (Aβ) peptides into amyloid-β fibrils (Aβ fibrils). To disrupt the remodeling of Aβ fibrils, a number of candidate molecules have been proposed. To study the molecular mechanisms of Aβ fibrils remodeling we performed a series of all-atom molecular dynamics simulations, a total time of 3µs, in explicit solvent. Several previously undiscovered candidate molecule-Aβ fibrils binding modes are unraveled; one of which shows the direct conformational change of the Aβ fibril by understanding the physicochemical factors responsible for binding and subsequent remodeling of Aβ fibrils by the candidate molecule, open avenues into structure-based drug design for AD can be opened.

Keywords: alzheimer’s disease, amyloid, MD simulations, misfolded protein

Procedia PDF Downloads 321

Authors: Stephen Eyije Abechi, Casimir Emmanuel Gimba, Zaharaddeen Nasiru Garba, Sani Shamsudeen, David Ebuka Authur

Abstract:

The mechanisms of corrosion inhibition of mild steel in acid medium using Acalypha chamaedrifolia leaves extract as potential green inhibitor were investigated. Gravimetric (weight loss) technique was used for the corrosion studies. Mild steel coupons of 2cm × 1cm × 0.27 cm dimensions were exposed for varying durations of between 24 to 120 hours, in 1M HCl medium containing a varying concentrations of the leaves extract (0.25g/L, - 1.25g/L). The results show that corrosion rates dropped from a value of 0.49 mgcm-2hr-1 for the uninhibited medium to a value of 0.15 mgcm-2hr-1 for the inhibited medium of 1M HCl in 0.25 g/l of the extract. Values of corrosion inhibition efficiencies of 70.38-85.11% were observed as the concentration of the inhibitor were increased from 0.25g/L, - 1.25g/L. Corrosion Inhibition was found to increase with increase in immersion time and temperature. The magnitude of the Ea indicates that the interaction between the metal surface and the inhibitor was chemisorptions. The Adsorption process fit into the Langmuir isotherm model with a correlation coefficient of 0.97. Evidence from molecular dynamics model shows that Methyl stearate (Line 5) and (3Z, 13Z)-2-methyloctadeca-3,13-dien-1-ol (line 11) were found to have the highest binding energy of -197.69 ± 3.12 and-194.56 ± 10.04 in kcal/mol respectively. The binding energy of these compounds indicates that they would be a very good corrosion inhibitor for mild steel and other Fe related materials.

Keywords: binding energy, corrosion, inhibitor, Langmuir isotherm, mild steel.

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Authors: Jyh Sheen, Yong-Lin Wang

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This research dedicates to find a different measurement procedure of microwave dielectric properties of ceramic materials with high dielectric constants. For the composite of ceramic dispersed in the polymer matrix, the dielectric constants of the composites with different concentrations can be obtained by various mixture equations. The other development of mixture rule is to calculate the permittivity of ceramic from measurements on composite. To do this, the analysis method and theoretical accuracy on six basic mixture laws derived from three basic particle shapes of ceramic fillers have been reported for dielectric constants of ceramic less than 40 at microwave frequency. Similar researches have been done for other well-known mixture rules. They have shown that both the physical curve matching with experimental results and low potential theory error are important to promote the calculation accuracy. Recently, a modified of mixture equation for high dielectric constant ceramics at microwave frequency has also been presented for strontium titanate (SrTiO3) which was selected from five more well known mixing rules and has shown a good accuracy for high dielectric constant measurements. However, it is still not clear the accuracy of this modified equation for other high dielectric constant materials. Therefore, the five more well known mixing rules are selected again to understand their application to other high dielectric constant ceramics. The other high dielectric constant ceramic, TiO2 with dielectric constant 100, was then chosen for this research. Their theoretical error equations are derived. In addition to the theoretical research, experimental measurements are always required. Titanium dioxide is an interesting ceramic for microwave applications. In this research, its powder is adopted as the filler material and polyethylene powder is like the matrix material. The dielectric constants of those ceramic-polyethylene composites with various compositions were measured at 10 GHz. The theoretical curves of the five published mixture equations are shown together with the measured results to understand the curve matching condition of each rule. Finally, based on the experimental observation and theoretical analysis, one of the five rules was selected and modified to a new powder mixture equation. This modified rule has show very good curve matching with the measurement data and low theoretical error. We can then calculate the dielectric constant of pure filler medium (titanium dioxide) by those mixing equations from the measured dielectric constants of composites. The accuracy on the estimating dielectric constant of pure ceramic by various mixture rules will be compared. This modified mixture rule has also shown good measurement accuracy on the dielectric constant of titanium dioxide ceramic. This study can be applied to the microwave dielectric properties measurements of other high dielectric constant ceramic materials in the future.

Keywords: microwave measurement, dielectric constant, mixture rules, composites

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Authors: Mohd Javaid, Shahbaz Khan, Abid Haleem

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Purpose: Large numbers of 3D printing technologies are now available for sophisticated applications in different fields. Additive manufacturing has established its dominance in design, development, and customisation of the product. In the era of developing technologies, there is a need to identify the appropriate technology for different application. In order to fulfil this need, two widely used printing technologies such as Fused Deposition Modeling (FDM), and Binding-Jet 3D Printing are compared for effective utilisation in the current scenario for different applications. Methodology: Systematic literature review conducted for both technologies with applications and associated factors enabling for the same. Appropriate MCDM tool is used to compare critical factors for both the technologies. Findings: Both technologies have their potential and capabilities to provide better direction to the industry. Additionally, this paper is helpful to develop a decision support system for the proper selection of technologies according to their continuum of applications and associated research and development capability. The vital issue is raw materials, and research-based material development is key to the sustainability of the developed technologies. FDM is a low-cost technology which provides high strength product as compared to binding jet technology. Researcher and companies can take benefits of this study to achieve the required applications in lesser resources. Limitations: Study has undertaken the comparison with the opinion of experts, which may not always be free from bias, and some own limitations of each technology. Originality: Comparison between these technologies will help to identify best-suited technology as per the customer requirements. It also provides development in this different field as per their extensive capability where these technologies can be successfully adopted. Conclusion: FDM and binding jet technology play an active role in industrial development. These help to assist the customisation and production of personalised parts cost-effectively. So, there is a need to understand how these technologies can provide these developments rapidly. These technologies help in easy changes or in making revised versions of the product, which is not easily possible in the conventional manufacturing system. High machine cost, the requirement of skilled human resources, low surface finish, and mechanical strength of product and material changing option is the main limitation of this technology. However, these limitations vary from technology to technology. In the future, these technologies are to be commercially viable for efficient usage in direct manufacturing of varied parts.

Keywords: 3D printing, comparison, fused deposition modeling, FDM, binding jet technology

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Authors: Mohammad Hossein Modarressi, Mozhgan Mondeali, Khabat Barkhordari, Ali Etemadi

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The COVID-19 pandemic, caused by SARS-CoV-2, has led to significant concerns worldwide due to its catastrophic effects on public health. The SARS-CoV-2 infection is initiated with the binding of the receptor-binding domain (RBD) in its spike protein to the ACE2 receptor in the host cell membrane. Due to the error-prone entity of the viral RNA-dependent polymerase complex, the virus genome, including the coding region for the RBD, acquires new mutations, leading to the appearance of multiple variants. These variants can potentially impact transmission, virulence, antigenicity and evasive immune properties. S477N mutation located in the RBD has been observed in the SARS-CoV-2 omicron (B.1.1. 529) variant. In this study, we investigated the consequences of S477N mutation at the molecular level using computational approaches such as molecular dynamics simulation, protein-protein interaction analysis, immunoinformatics and free energy computation. We showed that displacement of Ser with Asn increases the stability of the spike protein and its affinity to ACE2 and thus increases the transmission potential of the virus. This mutation changes the folding and secondary structure of the spike protein. Also, it reduces antibody neutralization, raising concern about re-infection, vaccine breakthrough and therapeutic values.

Keywords: S477N, COVID-19, molecular dynamic, SARS-COV2 mutations

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Authors: Rabia Saleem

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This research has a recently proposed strategy to find the exact inflationary solution of the Friedman equations in the context of the Rastall theory of gravity (RTG), known as constant-roll warm inflation, including dissipation effects. We establish the model to evaluate the effective potential of inflation and entropy. We develop the inflationary observable like scalar-tensor power spectra, scalar-tensor spectral indices, tensor-to-scalar ratio, and running of spectral-index. The theory parameter $\lambda$ is constrained to observe the compatibility of our model with Planck 2013, Planck TT, TE, EE+lowP (2015), and Planck 2018 bounds. The results are feasible and interesting up to the 2$\sigma$ confidence level.

Keywords: modified gravity, warm inflation, constant-roll limit, dissipation

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Authors: Sariah Abang, S. M. Anisuzzaman, Awang Bono, D. Krishnaiah, S. Rasmih

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Biodiesel is a potential renewable energy due to biodegradable and non-toxic. The challenge of its commercialization is associated with high production cost due to its feedstock also useful in various food products. Non-competitive feedstock such as waste cooking oils normally contains a large amount of free fatty acids (FFAs). Large amount of fatty acid degrades the alkaline catalyst in the biodiesel production, thereby decreasing the biodiesel production rate. Generally, biodiesel production processes including esterification and trans-esterification are conducting in a mixed system, in which the hydrodynamic effect on the reaction could not be completely defined. The aim of this study was to investigate the effect of variation rate constant and activation energy on energy consumption of biodiesel production. Usually, the changes of rate constant and activation energy depend on the operating temperature and the degradation of catalyst. By varying the activation energy and kinetic rate constant, the effects can be seen on the energy consumption of biodiesel production. The result showed that the energy consumption of biodiesel is dependent on the changes of rate constant and activation energy. Furthermore, this study was simulated using Aspen HYSYS.

Keywords: methanol, palm oil, simulation, transesterification, triolein

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Authors: Sumeyra Sevim, Gulsum Gizem Topal, Mercan Merve Tengilimoglu-Metin, Mevlude Kizil

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Aflatoxin M1 (AFM1) is a major toxic and carcinogenic molecule in milk and milk products. Therefore, it poses a risk for public health. Probiotics can be biological agent to remove AFM1. The aim of this study is to evaluate the effect of probiotic bacteria on AFM1 detoxification in phosphate buffer saline. The PBS samples artificially contaminated with AFM1 at concentration 100 pg/ml were prepared with probiotics bacteria that including monoculture (L. plantarum, B. bifidum ATCC, B. animalis ATCC 27672) and binary culture (L. bulgaricus + S. thermophiles, B. bifidum ATCC + B. animalis ATCC 27672, L. plantarum+B. bifidum ATCC, L. plantarum+ B. animalis ATCC 27672). The samples were incubated at 37°C for 4 hours and stored for 1, 5 and 10 days. The toxin was measured by the ELISA. The highest levels of AFM1 binding ability (63.6%) in PBS were detected yoghurt starter bacteria, while L. plantarum had the lowest levels of AFM1 binding ability (35.5%) in PBS. In addition, it was found that there was significant effect of storage on AFM1 binding ability in all groups except the one including B. animalis (p < 0.05). Consequently, results demonstrate that AFM1 detoxification by probiotic bacteria has a potential application to reduce toxin concentrations in yoghurt. Moreover, probiotic strains can react with itself as synergic or antagonist.

Keywords: aflatoxin M1, ELISA, probiotics, storage

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Authors: Mustafa Ali Abugila, Basma Nuri Kajruba, Hanan Elhadi, Rehab Ramadan Wali

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Iron deficiency anemia is characterized by a decrease of Hb (hemoglobin), serum iron, ferritin, and RBC (red blood cells) (shape and size). Also, it is characterized by an increase in total iron binding capacity (TIBC). Red blood cells become microctytic and hypochromic due to a decrease in iron content. This study was conducted in the north west of Libya and included 210 women in childbearing age (18-45 years) who were visiting women clinic. After filling the questionnaire, blood samples were taken and analyzed for hematological and biochemical profiles. Biochemical tests included measurement of serum iron, ferritin, and total iron binding capacity (TIBC). Among the total sample (210 women), there were 87 (41.42%) pregnant and 123 (58.57%) non-pregnant women (includes married and single). Pregnant women (87) were classified according to the gestational age into first, second, and third trimesters. The means of biochemical and hematological parameters in the studied samples were: Hb = 10.37± 2.02 g/dl, RBC = 3.78± 1.037 m/m3, serum iron 61.86± 40.28 µg/dl, and TIBC = 386.01 ± 94.91 µg/dl. In this study, we considered that any women have hemoglobin below 11.5 g/dl is anemic. 89.1%, 69.5%, and 47.8% of pregnant women who belong to third trimester had low (below normal value) Hb, serum iron, and ferritin, i.e. iron deficiency anemia was more common in third trimester among the first and the second trimesters. Third trimester pregnant women also had high TIBC more than first and second trimesters.

Keywords: red blood cells, hemoglobin, total iron binding capacity, ferritin

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Authors: Anika Chebrolu

Abstract:

Mono-targeted drugs can be of limited efficacy against complex diseases. Recently, multi-target drug design has been approached as a promising tool to fight against these challenging diseases. However, the scope of current computational approaches for multi-target drug design is limited. DeepLig presents a de-novo drug discovery platform that uses reinforcement learning to generate and optimize novel, potent, and multitargeted drug candidates against protein targets. DeepLig’s model consists of two networks in interplay: a generative network and a predictive network. The generative network, a Stack- Augmented Recurrent Neural Network, utilizes a stack memory unit to remember and recognize molecular patterns when generating novel ligands from scratch. The generative network passes each newly created ligand to the predictive network, which then uses multiple Graph Attention Networks simultaneously to forecast the average binding affinity of the generated ligand towards multiple target proteins. With each iteration, given feedback from the predictive network, the generative network learns to optimize itself to create molecules with a higher average binding affinity towards multiple proteins. DeepLig was evaluated based on its ability to generate multi-target ligands against two distinct proteins, multi-target ligands against three distinct proteins, and multi-target ligands against two distinct binding pockets on the same protein. With each test case, DeepLig was able to create a library of valid, synthetically accessible, and novel molecules with optimal and equipotent binding energies. We propose that DeepLig provides an effective approach to design multi-targeted drug therapies that can potentially show higher success rates during in-vitro trials.

Keywords: drug design, multitargeticity, de-novo, reinforcement learning

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Authors: Hari Bezwada, Michelle Cheon, Ryan Divan, Hannah Escritor, Michelle Kagramian, Isha Korgaonkar, Maya MacAdams, Udgita Pamidigantam, Richard Pilny, Eleanor Race, Angadh Singh, Nathan Zhang, LeeAnn Nguyen, Fina Liotta

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Malaria is a deadly disease caused by the Plasmodium parasite, which continues to develop resistance to current antimalarial drugs. In this research project, the effectiveness of numerous thiazole derivatives was explored in inhibiting the PfPKG, a crucial part of the Plasmodium life cycle. This study involved the synthesis of six thiazole-derived amides to inhibit the PfPKG pathway. Nuclear Magnetic Resonance (NMR) spectroscopy and Infrared (IR) spectroscopy were used to characterize these compounds. Furthermore, AutoDocking software was used to predict binding affinities of these thiazole-derived amides in silico. In silico, compound 6 exhibited the highest predicted binding affinity to PfPKG, while compound 5 had the lowest affinity. Compounds 1-4 displayed varying degrees of predicted binding affinity. In-vitro, it was found that compound 4 had the best percent inhibition, while compound 5 had the worst percent inhibition. Overall, all six compounds had weak inhibition (approximately 30-39% at 10 μM), but these results provide a foundation for future drug discovery experiments.

Keywords: Medicinal Chemistry, Malaria, drug discovery, PfPKG, Thiazole, Plasmodium

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Authors: Youji Miyake

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In aircraft assembly, a large number of preparatory holes are required for screw and rivet joints. Currently, many holes are drilled manually because it is difficult to machine the holes using conventional computerized numerical control(CNC) machines. The application of industrial robots to drill the hole has been considered as an alternative to the CNC machines. However, the rigidity of robot arms is so low that vibration is likely to occur during drilling. In this study, it is proposed constant-load feed machining as a method to perform high-precision drilling while minimizing the thrust force, which is considered to be the cause of vibration. In this method, the drill feed is realized by a constant load applied onto the tool so that the thrust force is theoretically kept below the applied load. The performance of the proposed method was experimentally examined through the deep hole drilling of plastic and simultaneous drilling of metal/plastic stack plates. It was confirmed that the deep hole drilling and simultaneous drilling could be performed without generating vibration by controlling the tool feed rate in the appropriate range.

Keywords: constant load feed machining, robotic drilling, deep hole, simultaneous drilling

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Authors: Tayyaba Ghani, Mazhar Mehmood, Mohammad Mujahid

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TiO₂ nanotubes are receiving immense attraction in the field of dye-sensitized solar cells due to their well-defined nanostructures, efficient electron transport and large surface area as compared to other one dimensional structures. In the present work, we have investigated the influence of temperature on the morphology of anodically produced self-organized Titanium oxide nanotubes (TiNTs). TiNTs are synthesized by two-step anodization method in an ethylene glycol based electrolytes containing ammonium fluoride. Experiments are performed at constant anodization voltage for two hours. An investigation by the SEM images reveals that if the temperature is kept constant during the anodizing experiment, variation in the average tube diameter is significantly reduced. However, if the temperature is not controlled then due to the exothermic nature of reactions for the formation of TiNTs, the temperature of electrolyte keep on increasing. This variation in electrolyte bath temperature introduced strong variations in tube diameter (20 nm to 160 nm) along the length of tubes. Current profiles, recorded during the anodization experiment, predict the effect of constant and varying experimental temperatures as well. In both cases, XRD results show the complete anatase crystal structure of nanotube upon annealing at 450 °C. Present work highlights the importance of constant temperature during the anodization experiments in order to develop an ordered array of nanotubes with a uniform tube diameter.

Keywords: anodization, ordering, temperature, TiO₂ nanotubes

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Authors: Chinmayee Choudhury

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Human Melanocortin 4 Receptor (HMC4R) is one of the most potential drug targets for the treatment of obesity which controls the appetite. A deletion of the residues 88-92 in HMC4R is sometimes the cause of severe obesity in the humans. In this study, two homology models are constructed for the normal as well as mutated HMC4Rs and some phytochemicals present in Green Tea, Honey and Cinnamon have been docked to them to study their differential binding to the normal and mutated HMC4R as compared to the natural agonist α- MSH. Two homology models have been constructed for the normal as well as mutated HMC4Rs using the Modeller9v7. Some of the phytochemicals present in Green Tea, Honey, and Cinnamon, which have appetite suppressant activities are constructed, minimized and docked to these normal and mutated HMC4R models using ArgusLab 4.0.1. The mode of binding of the phytochemicals with the Normal and Mutated HMC4Rs have been compared. Further, the mode of binding of these phytochemicals with that of the natural agonist α- Melanocyte Stimulating Hormone(α-MSH) to both normal and mutated HMC4Rs have also been studied. It is observed that the phytochemicals Kaempherol, Epigallocatechin-3-gallate (EGCG) present in Green Tea and Honey, Isorhamnetin, Chlorogenic acid, Chrysin, Galangin, Pinocambrin present in Honey, Cinnamaldehyde, Cinnamyl acetate and Cinnamyl alcohol present in Cinnamon have capacity to form more stable complexes with the Mutated HMC4R as compared to α- MSH. So they may be potential agonists of HMC4R to suppress the appetite.

Keywords: HMC4R, α-MSH, docking, photochemical, appetite suppressant, homology modelling

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Authors: H. Abu-Ali, A. Nabok, T. Smith

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Aptamers are single-strand of DNA or RNA nucleotides sequence which is designed in vitro using selection process known as SELEX (systematic evolution of ligands by exponential enrichment) were developed for the selective detection of many toxic materials. In this work, we have developed an electrochemical biosensor for highly selective and sensitive detection of Hg2+ and Pb2+ using a specific aptamer probe (SAP) labelled with ferrocene (or methylene blue) in (5′) end and the thiol group at its (3′) termini, respectively. The SAP has a specific coil structure that matching with G-G for Pb2+ and T-T for Hg2+ interaction binding nucleotides ions, respectively. Aptamers were immobilized onto surface of screen-printed gold electrodes via SH groups; then the cyclic voltammograms were recorded in binding buffer with the addition of the above metal salts in different concentrations. The resulted values of anode current increase upon binding heavy metal ions to aptamers and analyte due to the presence of electrochemically active probe, i.e. ferrocene or methylene blue group. The correlation between the anodic current values and the concentrations of Hg2+ and Pb2+ ions has been established in this work. To the best of our knowledge, this is the first example of using a specific DNA aptamers for electrochemical detection of heavy metals. Each increase in concentration of 0.1 μM results in an increase in the anode current value by simple DC electrochemical test i.e (Cyclic Voltammetry), thus providing an easy way of determining Hg2+ and Pb2+concentration.

Keywords: aptamer, based, biosensor, DNA, electrochemical, highly, specific

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Authors: Mohd Farooq Naqshbandi

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The four fractions of aqueous extract of Sesame Seeds (Sesamum indicum L.) were studied for invitro DNA fragmentation, cell migration, and cellular apoptosis on SW480 and HTC116 human colorectal cancer cell lines. The seeds of Sesamum indicum were extracted with six solvents, including Methanol, Ethanol, Aqueous, Chloroform, Acetonitrile, and Hexane. The aqueous extract (IC₅₀ value 154 µg/ml) was found to be the most active in terms of cytotoxicity with SW480 human colorectal cancer cell lines. Further fractionation of this aqueous extract on flash chromatography gave four fractions. These four fractions were studied for anticancer and DNA binding studies. Cell viability was assessed by colorimetric assay (MTT). IC₅₀ values for all these four fractions ranged from 137 to 548 µg/mL for the HTC116 cancer cell line and 141 to 402 µg/mL for the SW480 cancer cell line. The four fractions showed good anticancer and DNA binding properties. The DNA binding constants ranged from 10.4 ×10⁴ 5 to 28.7 ×10⁴, showing good interactions with DNA. The DNA binding interactions were due to intercalative and π-π electron forces. The results indicate that aqueous extract fractions of sesame showed inhibition of cell migration of SW480 and HTC116 human colorectal cancer cell lines and induced DNA fragmentation and apoptosis. This was demonstrated by calculating the low wound closure percentage in cells treated with these fractions as compared to the control (80%). Morphological features of nuclei of cells treated with fractions revealed chromatin compression, nuclear shrinkage, and apoptotic body formation, which indicate cell death by apoptosis. The flow cytometer of fraction-treated cells of SW480 and HTC116 human colorectal cancer cell lines revealed death due to apoptosis. The results of the study indicate that aqueous extract of sesame seeds may be used to treat colorectal cancer.

Keywords: Sesamum indicum, cell migration inhibition, apoptosis induction, anticancer activity, colorectal cancer

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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: Nihar Ranjan, Derrick Watkins, Dev P. Arya

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Current methods in the study of antibiotic activity of ribosome targeted antibiotics are dependent on cell based bacterial inhibition assays or various forms of ribosomal binding assays. These assays are typically independent of each other and little direct correlation between the ribosomal binding and bacterial inhibition is established with the complementary assay. We have developed novel high-throughput capable assays for ribosome targeted drug discovery. One such assay examines the compounds ability to bind to a model ribosomal RNA A-site. We have also coupled this assay to other functional orthogonal assays. Such analysis can provide valuable understanding of the relationships between two complementary drug screening methods and could be used as standard analysis to correlate the affinity of a compound for its target and the effect the compound has on a cell.

Keywords: bacterial resistance, aminoglycosides, screening, drugs

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Authors: Larbi Hammadi, N. Boudjenane, N. Benhallou, R. Houjedje, R. Reffis, M. Belhadri

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Many of clays exhibited the thixotropic behavior in which, the apparent viscosity of material decreases with time of shearing at constant shear rate. The structural kinetic model (SKM) was used to characterize the thixotropic behavior of two different kinds of clays used in fabrication of ceramic. Clays selected for analysis represent the fluid and semisolid clays materials. The SKM postulates that the change in the rheological behavior is associated with shear-induced breakdown of the internal structure of the clays. This model for the structure decay with time at constant shear rate assumes nth order kinetics for the decay of the material structure with a rate constant.

Keywords: ceramic, clays, structural kinetic model, thixotropy, viscosity

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Authors: Natalia Caldeira De Carvalho, Tassia Batista Pessato, Luis Gustavo R. Fernandes, Ricardo L. Zollner, Flavia Maria Netto

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Protein hydrolysates are ingredients of enteral diets and hypoallergenic formulas. Enzymatic hydrolysis is the most commonly used method for reducing the antigenicity of milk protein. The antigenicity and physicochemical characteristics of the protein hydrolysates depend on the reaction parameters. Among them, pH has been pointed out as of the major importance. Hydrolysis reaction in laboratory scale is commonly carried out under controlled pH (pH-stat). However, from the industrial point of view, controlling pH during hydrolysis reaction may be infeasible. This study evaluated the impact of pH control on the physicochemical properties and antigenicity of the hydrolysates of whey proteins with Alcalase. Whey protein isolate (WPI) solutions containing 3 and 7 % protein (w/v) were hydrolyzed with Alcalase 50 and 100 U g-1 protein at 60°C for 180 min. The reactions were carried out under controlled and uncontrolled pH conditions. Hydrolyses performed under controlled pH (pH-stat) were initially adjusted and maintained at pH 8.5. Hydrolyses carried out without pH control were initially adjusted to pH 8.5. Degree of hydrolysis (DH) was determined by OPA method, peptides profile was evaluated by HPLC-RP, and molecular mass distribution by SDS-PAGE/Tricine. The residual α-lactalbumin (α-La) and β-lactoglobulin (β-Lg) concentrations were determined using commercial ELISA kits. The specific IgE and IgG binding capacity of hydrolysates was evaluated by ELISA technique, using polyclonal antibodies obtained by immunization of female BALB/c mice with α-La, β-Lg and BSA. In hydrolysis under uncontrolled pH, the pH dropped from 8.5 to 7.0 during the first 15 min, remaining constant throughout the process. No significant difference was observed between the DH of the hydrolysates obtained under controlled and uncontrolled pH conditions. Although all hydrolysates showed hydrophilic character and low molecular mass peptides, hydrolysates obtained with and without pH control exhibited different chromatographic profiles. Hydrolysis under uncontrolled pH released, predominantly, peptides between 3.5 and 6.5 kDa, while hydrolysis under controlled pH released peptides smaller than 3.5 kDa. Hydrolysis with Alcalase under all conditions studied decreased by 99.9% the α-La and β-Lg concentrations in the hydrolysates detected by commercial kits. In general, β-Lg concentrations detected in the hydrolysates obtained under uncontrolled pH were significantly higher (p<0.05) than those detected in hydrolysates produced with pH control. The anti-α-La and anti-β-Lg IgE and IgG responses to all hydrolysates decreased significantly compared to WPI. Levels of specific IgE and IgG to the hydrolysates were below 25 and 12 ng ml-1, respectively. Despite the differences in peptide composition and α-La and β-Lg concentrations, no significant difference was found between IgE and IgG binding capacity of hydrolysates obtained with or without pH control. These results highlight the impact of pH on the hydrolysates characteristics and their concentrations of antigenic protein. Divergence between the antigen detection by commercial ELISA kits and specific IgE and IgG binding response was found in this study. This result shows that lower protein detection does not imply in lower protein antigenicity. Thus, the use of commercial kits for allergen contamination analysis should be cautious.

Keywords: allergy, enzymatic hydrolysis, milk protein, pH conditions, physicochemical characteristics

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Authors: Marsden Jacques, Dennis Wong

Abstract:

A weak order is a way to rank n objects where ties are allowed. In this talk, we present a recursive framework to generate Gray codes for weak orders. We then describe a simple algorithm based on the framework that generates 2-Gray codes for weak orders in constant amortized time per string. This framework can easily be modified to generate other Gray codes for weak orders. We provide an example on using the framework to generate the first Shift Gray code for weak orders, also in constant amortized time, where consecutive strings differ by a shift or a symbol change.

Keywords: weak order, Cayley permutation, Gray code, shift Gray code

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Authors: Zahid Manzoor, Shaukat Hussain Munawar, Zahid Iqbal, Imran Ahmad Khan, Abdul Aziz, Hafiz Muhammad Qasim

Abstract:

The present study was aimed to investigate the pharmacokinetics behavior and optimal dosage regimen of danofloxacin in 8 adult healthy buffaloes of local breed (Nili Ravi) following single intravenous administration at the dose of 2.5 mg/kg body weight. Plasma drug concentrations at various time intervals were measured by HPLC method. In vitro plasma protein binding was determined employing the ultrafiltration technique. The distribution and elimination of danofloxacin was rapid, as indicated by the values (Mean±SD) of distribution half-life (t1/2α = 0.25±0.09 hours) and elimination half life (t1/2β = 3.26±0.43 hours), respectively. Volume of distribution at steady state (Vss) was 1.14±0.12 L/kg, displaying its extensive distribution into various body fluids and tissues. The high value of AUC (9.80±2.14 µg/ml.hr) reflected the vast area of the body covered by drug concentration. The mean residence time was noted to be 4.78±0.52 hours. On the basis of pharmacokinetic parameters, a suitable intravenous regimen for danofloxacin in adult buffaloes would be 6.5 mg/kg to be repeated after 12 hours intervals. The present study is the foremost pharmacokinetic study of danofloxacin in the local species which would provide the valueable contribution in the local manufacturing of danofloxacin in Pakistan in future.

Keywords: danofloxacin, pharmacokinetics, plasma protein binding, buffaloes, dosage regimen

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Authors: Young Hee Geum

Abstract:

We propose the numerical method defined by xn+1 = xn − λ[f(xn − μh(xn))/]f'(xn) , n ∈ N, and determine the control parameter λ and μ to converge cubically. In addition, we derive the asymptotic error constant. Applying this proposed scheme to various test functions, numerical results show a good agreement with the theory analyzed in this paper and are proven using Mathematica with its high-precision computability.

Keywords: asymptotic error constant, iterative method, multiple root, root-finding

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Authors: Shagufta Tabassum, V. P. Pawar

Abstract:

The study of static dielectric properties in a binary mixture of 1,2 dichloroethane (DE) and n,n dimethylformamide (DMF) polar liquids has been carried out in the frequency range of 10 MHz to 30 GHz for 11 different concentration using time domain reflectometry technique at 10ºC temperature. The dielectric relaxation study of solute-solvent mixture at microwave frequencies gives information regarding the creation of monomers and multimers as well as interaction between the molecules of the binary mixture. The least squares fit method is used to determine the values of dielectric parameters such as static dielectric constant (ε₀), dielectric constant at high frequency (ε_∞) and relaxation time (τ).

Keywords: shagufta shaikhexcess parameters, relaxation time, static dielectric constant, time domain reflectometry

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Authors: Sakshi Piplani, Ajit Kumar

Abstract:

Valproic acid (VPA) is the first synthetic therapeutic agent used to treat epileptic disorders, which account for affecting nearly 1% world population. Teratogenicity caused by VPA has prompted the search for next generation drug with better efficacy and lower side effects. Recent studies have posed HDAC8 as direct target of VPA that causes the teratogenic effect in foetus. We have employed molecular dynamics (MD) and docking simulations to understand the binding mode of VPA and their analogues onto HDAC8. A total of twenty 3D-structures of human HDAC8 isoforms were selected using BLAST-P search against PDB. Multiple sequence alignment was carried out using ClustalW and PDB-3F07 having least missing and mutated regions was selected for study. The missing residues of loop region were constructed using MODELLER and energy was minimized. A set of 216 structural analogues (>90% identity) of VPA were obtained from Pubchem and ZINC database and their energy was optimized with Chemsketch software using 3-D CHARMM-type force field. Four major neurotransmitters (GABAt, SSADH, α-KGDH, GAD) involved in anticonvulsant activity were docked with VPA and its analogues. Out of 216 analogues, 75 were selected on the basis of lower binding energy and inhibition constant as compared to VPA, thus predicted to have anti-convulsant activity. Selected hHDAC8 structure was then subjected to MD Simulation using licenced version YASARA with AMBER99SB force field. The structure was solvated in rectangular box of TIP3P. The simulation was carried out with periodic boundary conditions and electrostatic interactions and treated with Particle mesh Ewald algorithm. pH of system was set to 7.4, temperature 323K and pressure 1atm respectively. Simulation snapshots were stored every 25ps. The MD simulation was carried out for 20ns and pdb file of HDAC8 structure was saved every 2ns. The structures were analysed using castP and UCSF Chimera and most stabilized structure (20ns) was used for docking study. Molecular docking of 75 selected VPA-analogues with PDB-3F07 was performed using AUTODOCK4.2.6. Lamarckian Genetic Algorithm was used to generate conformations of docked ligand and structure. The docking study revealed that VPA and its analogues have more affinity towards ‘hydrophobic active site channel’, due to its hydrophobic properties and allows VPA and their analogues to take part in van der Waal interactions with TYR24, HIS42, VAL41, TYR20, SER138, TRP137 while TRP137 and SER138 showed hydrogen bonding interaction with VPA-analogues. 14 analogues showed better binding affinity than VPA. ADMET SAR server was used to predict the ADMET properties of selected VPA analogues for predicting their druggability. On the basis of ADMET screening, 09 molecules were selected and are being used for in-vivo evaluation using Danio rerio model.

Keywords: HDAC8, docking, molecular dynamics simulation, valproic acid

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Authors: Bongmun Kang, Kagnari Yamakawa, Yoshihisa Hagihara, Yuji Ito, Michimasa Kishimoto, Yoichi Kumada

Abstract:

The PMMA-tag was genetically fused with the C-terminal region of VHH molecules. This antibody, VHH, is known as a single-chain domain, which is devoid of light chains. The PMMA-tag, which could affect the isoelectric point (pI) changeable with a charge of amino acid in VHHs were closely related to the solubility of VHH molecules during refolding. The genetic fusion of PMMA-tag to C-terminal region of VHHs significantly affects the recovery of their soluble protein during refolding by 50 mM TAPS at pH 8.5. It could be refolded with a recovery of more than 95% by dialysis at pH 8.5. A marked difference in the antigen-binding activities in the adsorption state was significantly high in VHH-PM compared to the wild type of VHH. There are approximately 8-fold differences in the antigen-binding activities in the adsorption state between VHH-PM and VHH.

Keywords: VHH, PMMA-tag, isoelectric point, pH, Solubility, refolding, immobilization, ELISA

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Authors: Naseer Iqbal, Mukesh Kumar, Pradeep Sharma, Satya Prakash Yadav, Punit Kaur, Sujata Sharma, T. P. Singh

Abstract:

Dehydroquinase (3-dehydroquinate dehydratase, DHQD, EC 4.2.1.10) is involved in shikimate pathway and catalyzes the conversion of dehydroquinate to dehydroshikimate. Shikimate pathway is important drug target as this pathway is absent in mammals. DHQD from Acinetobacter baumannii (AbDHQD) was cloned, expressed and purified to homogeneity. The binding studies showed that compounds quinic acid and citrazinic acid bound to AbDHQD at micromolar concentrations. AbDHQD was crystallized using 30% PEG-3350, 50mM tris-HCl, and 1.0M MgSO4 at PH 8.0. Crystals of AbDHQD were stabilized by transferring them into reservoir solution to which 25% glycerol was added for data collection at 100K. The X-ray intensity data were collected to 2.0Å resolution. The crystals belong to monoclinic space group P21 with cell dimensions, a = 82.3, b = 95.3, c = 132.3Å and β = 95.7°. The structure was solved with molecular replacement method and refined to Rcryst/Rfree factors of 0.200/0.232. The structures of 12 crystallographically independent molecules in the asymmetry unit were identical with r.m.s shifts for the C atoms ranging from 0.3 Å to 0.8 Å. They formed a dodecamer with four trimers arranged in a tetrahedral manner. The classical lid adopted an open conformation although a sulfate ion was observed in the substrate binding site. As a result of which, the compounds quinic acid and citrazinic acid did not bind to AbDHQD.

Keywords: acinetobacter Bauman Nii, dehydroquinate dehydratase, dodecamer, open conformation

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