Search results for: molecular descriptor

Authors: Hassan Nour, Nouh Mounadi, Oussama Abchir, Belaidi Salah, Samir Chtita

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Cholinesterase enzymes are biological catalysts essential for the transformation of acetylcholine, which is a neurotransmitter implicated in memory and learning, into acetic acid and choline, altering the neurotransmission process in Alzheimer’s disease patients. Therefore, inhibition of cholinesterase enzymes is a relevant strategy for the symptomatic treatment of Alzheimer’s disease. The current investigation aims to explore potential Cholinesterase (ChE) inhibitors through a comprehensive computational approach. Forty-nine phytoconstituents extracted from Cannabis sativa L were in-silico screened using molecular docking, pharmacokinetic and toxicological analysis to evaluate their possible inhibitory effect towards the cholinesterase enzymes. Two phytoconstituents belonging to cannabinoid derivatives were revealed to be promising candidates for Alzheimer therapy by acting as cholinesterase inhibitors. They have exhibited high binding affinities towards the cholinesterase enzymes and showed their ability to interact with key residues involved in cholinesterase enzymatic activity. In addition, they presented good ADMET profiles allowing them to be promising oral drug candidates. Furthermore, molecular dynamics (MD) simulations were executed to explore their interactions stability under mimetic biological conditions and thus support our findings. To corroborate the docking results, the binding free energy corresponding to the more stable ligand-ChE complexes was re-estimated by applying the MM-PBSA method. MD and MM-PBSA studies affirmed that the ligand-ChE recognition is spontaneous reaction leading to stable complexes. The conducted investigations have led to great findings that would strongly guide the pharmaceutical industries towards the rational development of potent anti-Alzheimer agents.

Keywords: alzheimer’s disease, molecular docking, cannabis sativa l, cholinesterase inhibitors

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Authors: O. J. Jesumoroti, Faridoon, R. Klein, K. A. Iobb, D. Mnkadhla, H. C. Hoppe, P. T. Kaye

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The 1, 3-aryl diketo acids (DKA) based agents represent an important class of HIV integrase (IN) strand transfer inhibitors. In other to study the chelating role of the divalent metal ion in the inhibition of IN strand transfer, we designed and synthesized a series of 2-hydroxy-3-oxo-3-phenyl propionate derivatives with the notion that such compounds could interact with the divalent ion in the active site of IN. The synthetic sequence to the desired compounds involves the concept of Doebner knoevenagel condensation, Fischer esterification and ketohydroxylation using neuclophilic re-oxidant; compounds were characterized by their IR, IHNMR, 13CNMR, HRMS spectroscopic data and melting point determination. Also, molecular docking was employed in this study and it was revealed that there is interaction with the active site of the enzyme. However, there is disparity in the corresponding anti-HIV activity determined by the experimental bioassay. These compounds lack potency at low micromolar concentration when compared to the results of the docking studies. Nevertheless, the results of the study suggest modification of the aryl ring with one or two hydroxyl groups to improve the inhibitory activity.

Keywords: anti-HIV-1 integrase, ketohydroxylation, molecular docking, propionate derivatives

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Authors: Tivani Phosa Mashamba-Thompson, Mahmoud E. S. Soliman

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To date, the cause of neurodegeneration is not well understood and diseases that stem from neurodegeneration currently have no known cures. Cathepsin B (CB) enzyme is known to be involved in the production of peptide neurotransmitters and toxic peptides in neurodegenerative diseases (NDs). CA-074Me is a membrane-permeable irreversible selective cathepsin B (CB) inhibitor as confirmed by in vivo studies. Due to the lack of the crystal structure, the binding mode of CA-074Me with the human CB at molecular level has not been previously reported. The main aim of this study is to gain an insight into the binding mode of CB CA-074Me to human CB using various computational tools. Herein, molecular dynamics simulations, binding free energy calculations and per-residue energy decomposition analysis were employed to accomplish the aim of the study. Another objective was to identify novel CB inhibitors based on the structure of CA-074Me using fragment based drug design using scaffold hoping drug design approach. Results showed that two of the designed ligands (hit 1 and hit 2) were found to have better binding affinities than the prototype inhibitor, CA-074Me, by ~2-3 kcal/mol. Per-residue energy decomposition showed that amino acid residues Cys29, Gly196, His197 and Val174 contributed the most towards the binding. The Van der Waals binding forces were found to be the major component of the binding interactions. The findings of this study should assist medicinal chemist towards the design of potential irreversible CB inhibitors.

Keywords: cathepsin B, scaffold hopping, docking, molecular dynamics, binding-free energy, neurodegerative diseases

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Authors: Supannika Klangphukhiew, Roongnapa Srichana, Rina Patramanon

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Cortisol has been used as a well-known commercial stress biomarker. A homeostasis response to psychological stress is indicated by an increased level of cortisol produced in hypothalamus-pituitary-adrenal (HPA) axis. Chronic psychological stress contributing to the high level of cortisol relates to several health problems. In this study, the cortisol biosensor was fabricated that mimicked the natural receptors. The artificial antibodies were prepared using molecular imprinted polymer technique that can imitate the performance of natural anti-cortisol antibody with high stability. Cortisol-molecular imprinted polymer (cortisol-MIP) was obtained using the multi-step swelling and polymerization protocol with cortisol as a target molecule combining methacrylic acid:acrylamide (2:1) with bisacryloyl-1,2-dihydroxy-1,2-ethylenediamine and ethylenedioxy-N-methylamphetamine as cross-linkers. Cortisol-MIP was integrated to the sensor. It was coated on the disposable screen-printed carbon electrode (SPCE) for portable electrochemical analysis. The physical properties of Cortisol-MIP were characterized by means of electron microscope techniques. The binding characteristics were evaluated via covalent patterns changing in FTIR spectra which were related to voltammetry response. The performance of cortisol-MIP modified SPCE was investigated in terms of detection range, high selectivity with a detection limit of 1.28 ng/ml. The disposable cortisol biosensor represented an application of MIP technique to recognize steroids according to their structures with feasibility and cost-effectiveness that can be developed to use in point-of-care.

Keywords: stress biomarker, cortisol, molecular imprinted polymer, screen-printed carbon electrode

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Authors: Desta Gebretekle Shiferaw, Balakrishna Kalluraya

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Oxadiazoles and their derivatives with thioether functionalities represent a new and exciting class of physiologically active heterocyclic compounds. Several molecules with these moieties play a vital role in pharmaceuticals because of their diverse biological activities. This paper describes a new class of 1,3,4- oxadiazole-2-thioethers with acetophenone, coumarin, and N-phenyl acetamide residues (S-alkylation), with the hope that the addition of various biologically active molecules will have a synergistic effect on anticancer activity. The structure of the synthesized title compounds was determined by the combined methods of IR, proton-NMR, carbon-13-NMR, and mass spectrometry. Further, all the newly prepared molecules were assessed against their antioxidant activity. Furthermore, four compounds were assessed for their molecular docking interactions and cytotoxicity activity. The synthesized derivatives have shown moderate antioxidant activity compared to the standard BHA. The IC50 of the tilted molecules (11b, 11c, 13b, and 14b) observed for in vitro anti-cancer activities were 11.20, 15.73, 59.61, and 27.66 g/ml at 72-hour treatment time against the A549 cell lines, respectively. The tested compounds' biological evaluation showed that 11b is the most effective molecule in the series.

Keywords: antioxidant activity, cytotoxicity activity, molecular docking, 1, 3, 4-Oxadiazole-2 thioether derivatives

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Authors: Bhuvanesh Baniya

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Alzheimer disease is illnesses that are responsible for neuronal cell death and resulting in lifelong cognitive problems. Due to their unclear mechanism, there are no effective drugs available for the treatment. For a long time, herbal drugs have been used as a role model in the field of the drug discovery process. Holy basil in the Indian medicinal system (Ayurveda) is used for several neuronal disorders like insomnia and memory loss for decades. This study aims to identify active components of holy basil as potential inhibitors for the treatment of Alzheimer disease. To fulfill this objective, the Network pharmacology approach, gene ontology, pharmacokinetics analysis, molecular docking, and molecular dynamics simulation (MDS) studies were performed. A total of 7 active components in holy basil, 12 predicted neurodegenerative targets of holy basil, and 8063 Alzheimer-related targets were identified from different databases. The network analysis showed that the top ten targets APP, EGFR, MAPK1, ESR1, HSPA4, PRKCD, MAPK3, ABL1, JUN, and GSK3B were found as significant target related to Alzheimer disease. On the basis of gene ontology and topology analysis results, APP was found as a significant target related to Alzheimer’s disease pathways. Further, the molecular docking results to found that various compounds showed the best binding affinities. Further, MDS top results suggested could be used as potential inhibitors against APP protein and could be useful for the treatment of Alzheimer’s disease.

Keywords: holy basil, network pharmacology, neurodegeneration, active phytochemicals, molecular docking and simulation

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Authors: Mojtaba Mirmontazemi, Habibollah Dadgar

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Bone is the most common metastasis site in some advanced malignancies, such as prostate and breast cancer. Bone metastasis generally indicates fewer prognostic factors in these patients. Different radiological and molecular imaging modalities are used for detecting bone lesions. Molecular imaging including computed tomography, magnetic resonance imaging, planar bone scintigraphy, single-photon emission tomography, and positron emission tomography as noninvasive visualization of the biological occurrences has the potential to exact examination, characterization, risk stratification and comprehension of human being diseases. Also, it is potent to straightly visualize targets, specify clearly cellular pathways and provide precision medicine for molecular targeted therapies. These advantages contribute implement personalized treatment for each patient. Currently, NaF PET/CT has significantly replaced standard bone scintigraphy for the detection of bone metastases. On one hand, 68Ga-PSMA PET/CT has gained high attention for accurate staging of primary prostate cancer and restaging after biochemical recurrence. On the other hand, FDG PET/CT is not commonly used in osseous metastases of prostate and breast cancer as well as its usage is limited to staging patients with aggressive primary tumors or localizing the site of disease. In this article, we examine current studies about FDG, NaF, and PSMA PET/CT images in bone metastases diagnostic utility and assess response to treatment in patients with breast and prostate cancer.

Keywords: skeletal metastases, fluorodeoxyglucose, sodium fluoride, molecular imaging, precision medicine, prostate cancer (68Ga-PSMA-11)

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Authors: Hind O. Osman, Tilal Elsaman, Bashir A. Yousef, Esraa Elhadi, Aimun A. E. Ahmed, Eyman Mohamed Eltayib, Malik Suliman Mohamed, Magdi Awadalla Mohamed

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Epilepsy is the most common neurological condition and cause of substantial morbidity and mortality. In the present study, the molecular hybridization tool was adopted to obtain six Schiff bases of isatin and adamantane-1-carbohydrazide (18–23). Then, their anticonvulsant activity was evaluated using a pentylenetetrazole- (PTZ-) induced seizure model using phenobarbitone as a positive control. Our findings showed that compounds 18–23 provided significant protection against PTZ-induced seizure, and maximum activities were associated with compound 23. Moreover, all investigated compounds increased the latency of induced convulsion and reduced the duration of epilepsy, with compound 23 being the best. Interestingly, most of the synthesized molecules showed a reduction in neurological symptoms and severity of the seizure. Molecular docking studies suggest GABA-A receptor as a potential target, and in silico ADME screening revealed that the pharmaceutical properties of compound 23 are within the specified limit. Thus, compound 23 was identified as a promising candidate that warrants further drug discovery processes.

Keywords: isatin and adamantane, anticonvulsant activity, PTZ-induced seizure, molecular docking

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Authors: Dong Xie, Jun Zhao, Yiming Weng

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One of the challenges in dental cement biomaterials is how to make a restorative with mechanical strengths and wear resistance that are comparable to contemporary dental resin composites. Currently none of the dental cement restoratives has been used in high stress-bearing sites due to their low mechanical strengths and poor wear-resistance. The objective of this study was to synthesize and characterize the poly(alkenoic acid)s with different molecular structures, use these polymers to formulate a dental cement restorative, and study the effect of molecular structures on reaction kinetics, viscosity, and mechanical strengths of the formed polymers and cement restoratives. In this study, poly(alkenoic acid)s with different molecular structures were synthesized. The purified polymers were formulated with commercial Fuji II LC glass fillers to form the experimental cement restoratives. The reaction kinetics was studied via 1HNMR spectroscopy. The formed restoratives were evaluated using compressive strength, diametral tensile strength, flexural strength, hardness and wear-resistance tests. Specimens were conditioned in distilled water at 37 oC for 24 h prior to testing. Fuji II LC restorative was used as control. The results show that the higher the arm number and initiator concentration, the faster the reaction was. It was also found that the higher the arm number and branching that the polymer had, the lower the viscosity of the polymer in water and the lower the mechanical strengths of the formed restorative. The experimental restoratives were 31-53% in compressive strength, 37-55% in compressive modulus, 80-126% in diametral tensile strength, 76-94% in flexural strength, 4-21% in fracture toughness and 53-96% in hardness higher than Fuji II LC. For wear test, the experimental restoratives were only 5.4-13% of abrasive and 6.4-12% of attritional wear depths of Fuji II LC in each wear cycle. The aging study also showed that all the experimental restoratives increased their strength continuously during 30 days, unlike Fuji II LC. It is concluded that polymer molecular structures have significant and positive impact on mechanical properties of dental cement restoratives.

Keywords: dental materials, polymers, strength, biomaterials

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Authors: Saule Mussabekova

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Forensic investigation of human teeth plays an important role in detection of crime, particularly in cases of personal identification of dead bodies changed by putrefactive processes or skeletonized bodies as well as when finding bodies of unknown persons. 152 teeth have been investigated; 85 of them belonged to men and 67 belonged to women taken from alive people of different age. Teeth have been investigated after extraction. Two types of teeth have been investigated: teeth without integrity violation of dental crown and teeth with different degrees of its violation. Additionally, 517 teeth have been investigated that were collected from dead bodies, 252 of which belonged to women and 265 belonged to men, whatever the cause of death with death limitation from 1 month to 20 years. Isohemagglutinating serums and Coliclons of different series have been used for the research of tooth-group specificity by serological methods according to the AB0 system. Standard protocols of different techniques have been used for DNA purification from teeth (by reagent Chelex 100 produced by Bio-Rad using reagent kit 'DNA IQTM System' produced by Promega company (USA) and using columns 'QIAamp DNA Investigator Kit' produced by Qiagen company). Results of comparative forensic investigation of human teeth using serological and molecular genetic methods have shown that use of serological methods for forensic identification is sensible only in cases of preselection prior to the next molecular genetic investigation as well as in cases of impossibility of corresponding genetic investigation for different objective reasons. A number of advantages of methods of molecular genetics in the dental investigation have been marked, particularly in putrefactive changes, in personal identification. Key moments of modern condition of personal identification have been reflected according to dental state. Prospective directions of advance preparation of material have been emphasized for identification of teeth in forensic practice.

Keywords: dental state, forensic identification, molecular genetic analysis, teeth

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Authors: C. Labate, M. P. De Santo, G. Lombardo, R. Barberi, M. Lombardo, N. M. Ziebarth

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In the past decades, the importance of corneal biomechanics in the normal and pathological functions of the eye has gained its credibility. In fact, the mechanical properties of biological tissues are essential to their physiological function. We are convinced that an improved understanding of the nanomechanics of corneal tissue is important to understand the basic molecular interactions between collagen fibrils. Ultimately, this information will help in the development of new techniques to cure ocular diseases and in the development of biomimetic materials. Therefore, nanotechnology techniques are powerful tools and, in particular, Atomic Force Microscopy has demonstrated its ability to reliably characterize the biomechanics of biological tissues either at the micro- or nano-level. In the last years, we have investigated the mechanical anisotropy of the human corneal stroma at both the tissue and molecular levels. In particular, we have focused on corneal cross-linking, an established procedure aimed at slowing down or halting the progression of the disease known as keratoconus. We have obtained the first evidence that riboflavin/UV-A corneal cross-linking induces both an increase of the elastic response and a decrease of the viscous response of the most anterior stroma at the scale of stromal molecular interactions.

Keywords: atomic force spectroscopy, corneal stroma, cross-linking, viscoelasticity

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Authors: K. R. Guna, Aldin Justin Sundararaj, B. C. Pillai, A. N. Subash

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A systematic study has been made for ignition delay times measurement behind a reflected shock wave for the low molecular weight hydrocarbon fuel in argon simulated gas mixtures. The low molecular hydrocarbon fuel–oxygen was diluted with argon for desired concentration is taken for the study. The suitability of the shock tube for measuring the ignition delay time is demonstrated by measuring the ignition delay for the liquefied petroleum gas for equivalence ratios (ф=0.5 & 1) in the temperature range 1150-1650 K. The pressure range was fixed from 5-15 bar. The ignition delay was measured by recording the ignition-induced pressure jump and emission from CH radical simultaneously. From conducting experiments, it was found that the ignition delay time for liquefied petroleum gas reduces with increase in temperature. The shock tube was calibrated for ethane-oxygen gas mixture and the results obtained from this study is compared with the earlier reported values and found to be comparably well suited for the measurement of ignition delay times. The above work was carried out using the shock tube facility at propulsion and high enthalpy laboratory, Karunya University.

Keywords: ignition delay, LPG, reflected shock, shock wave

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Authors: Imran Muhammad

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The main cause of infectious disease in the modern world is Mycobacterium Tuberculosis (MT). To combat tuberculosis, new and efficient drugs are an urgent need in the modern world. Schif bases are potent for their biological pharmacophore activity. Thus we selected different Vanillin-based Schiff bases for their binding activity against target enzymes of Mycobacterium tuberculosis that is (DprE1 (decaprenyl phosphoryl-β-D-ribose 2′-epimerase), and DNA gyrase subunit-A), using molecular docking. We evaluate the inhibition potential, interaction, and binding mode of these compounds with the target enzymes.

Keywords: schiff bases, tuberculosis, DNA gyrase, DprE1, docking

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Authors: Samy Madbouly

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The relaxation behavior of biorenewable castor oil-based polyurethane-lignin thin films synthesized in homogenous waterborne dispersions was investigated as a function of concentration at different temperatures and frequencies using broadband dielectric relaxation spectroscopy (BDRS). The molecular dynamics of the glass relaxation process and the local relaxation process of the PU-LS thin films were studied over a wide range of temperatures (-70 to 30 ℃) and frequencies (5 × 10−2 to 0.5 × 107 Hz) for different lignin concentration. Four relaxation processes have been observed namely; ?-, β-, γ-relaxations and ionic conductivity for pure castor oil-based PU and castor oil-lignin-based PU thin films at different temperatures and frequencies ranges. The Vogel-Fulcher-Tammann equation was found to be well described the temperature dependence of the characteristic relaxation times of the ?-relaxation process. However, on the other hand, the molecular dynamics of both β- and γ-relaxation processes were given by the Arrhenius equation. The incorporation of lignin into the castor oil-based PU significantly increased the glass transition temperature and primitivity of the thin films. In addition, the broadness, intensity, and molecular dynamics of the only observed ?-relaxation process were found to be strongly dependent on lignin concentration.

Keywords: castor oil, lignin, polyurethane, dielectric, dispersions

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Authors: Mera-Martínez Daniela

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Dendropsophus minutus, is a species distributed in South America including the slopes of the Andes, the Amazon basin, forests of southeastern Brazil and in Guyana where tropical forests are characteristic. The relationship of amphibians found in this locality is evidenced by molecular markers, with the objective of analyzing if the geographic distance is influencing the structure of the populations of D. minutus in Guyana; we analyzed 65 sequences from the 3 localities of Guyana where haplotype networks, Mantel Test and phylogeny were realized to know the influence. It was evidenced that there is a haplotypic difference in the locality of Guyana compared to Suriname and French Guyana, but this does not have a correlation with the geographic distance, but this one can be influenced by the conditions of the places.

Keywords: phylogeography, Dendropsophus, geographic distance, molecular markers

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Authors: Van Tran Thi Thuy, Dukjoon Kim

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A series of pH- and thermosensitive poly(N-isopropyl acrylamide-co-acrylic acid) were synthesized by radical polymerization and grafted on poly succinimide backbones. The poly succinimide derivatives synthesized were coated on iron oxide magnetic nanoparticles for potential applications in drug delivery systems with theranostic and molecular imaging. The structure of polymer shell was confirmed by FT-IR, H-NMR spectroscopies. Its thermal behavior was tested by UV-Vis spectroscopy. The particle size and its distribution are measured by dynamic light scattering (DLS) and transmission electron microscope (TEM). The mean diameter of the core-shell structure is from 20 to 80 nm.

Keywords: magnetic, nano, PNIPAM, polysuccinimide

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Authors: Paramita Banerjee, K. R. S. Chandrakumar, G. P. Das

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Bulk MgH2 has drawn much attention for the purpose of hydrogen storage because of its high hydrogen storage capacity (~7.7 wt %) as well as low cost and abundant availability. However, its practical usage has been hindered because of its high hydrogen desorption enthalpy (~0.8 eV/H2 molecule), which results in an undesirable desorption temperature of 3000C at 1 bar H2 pressure. To surmount the limitations of bulk MgH2 for the purpose of hydrogen storage, a detailed first-principles density functional theory (DFT) based study on the structure and stability of neutral (Mgm) and positively charged (Mgm+) Mg nanoclusters of different sizes (m = 2, 4, 8 and 12), as well as their interaction with molecular hydrogen (H2), is reported here. It has been found that due to the absence of d-electrons within the Mg atoms, hydrogen remained in molecular form even after its interaction with neutral and charged Mg nanoclusters. Interestingly, the H2 molecules do not enter into the interstitial positions of the nanoclusters. Rather, they remain on the surface by ornamenting these nanoclusters and forming new structures with a gravimetric density higher than 15 wt %. Our observation is that the inclusion of Grimme’s DFT-D3 dispersion correction in this weakly interacting system has a significant effect on binding of the H2 molecules with these nanoclusters. The dispersion corrected interaction energy (IE) values (0.1-0.14 eV/H2 molecule) fall in the right energy window, that is ideal for hydrogen storage. These IE values are further verified by using high-level coupled-cluster calculations with non-iterative triples corrections i.e. CCSD(T), (which has been considered to be a highly accurate quantum chemical method) and thereby confirming the accuracy of our ‘dispersion correction’ incorporated DFT calculations. The significance of the polarization and dispersion energy in binding of the H2 molecules are confirmed by performing energy decomposition analysis (EDA). A total of 16, 24, 32 and 36 H2 molecules can be attached to the neutral and charged nanoclusters of size m = 2, 4, 8 and 12 respectively. Ab-initio molecular dynamics (AIMD) simulation shows that the outermost H2 molecules are desorbed at a rather low temperature viz. 150 K (-1230C) which is expected. However, complete dehydrogenation of these nanoclusters occur at around 1000C. Most importantly, the host nanoclusters remain stable up to ~500 K (2270C). All these results on the adsorption and desorption of molecular hydrogen with neutral and charged Mg nanocluster systems indicate towards the possibility of reducing the dehydrogenation temperature of bulk MgH2 by designing new Mg-based nano materials which will be able to adsorb molecular hydrogen via this weak Mg-H2 interaction, rather than the strong Mg-H bonding. Notwithstanding the fact that in practical applications, these interactions will be further complicated by the effect of substrates as well as interactions with other clusters, the present study has implications on our fundamental understanding to this problem.

Keywords: density functional theory, DFT, hydrogen storage, molecular dynamics, molecular hydrogen adsorption, nanoclusters, physisorption

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Authors: K. Ali, M. F. Qamar, M. A. Zaman, M. Younus, I. Khan, S. Ehtisham-ul-Haque, R. Tamkeen, M. I. Rashid, Q. Ali

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This study centers on molecular identification of Haemonchus contortus and isolation of Benz-imidazoles (BZ) resistant strains. Different abattoirs’ of two geographic regions of Punjab (Pakistan) were frequently visited for the collection of worms. Out of 1500 (n=1500) samples that were morphologically confirmed as H. contortus, 30 worms were subjected to molecular procedures for isolation of resistant strains. Resistant worms (n=8) were further subjected to DNA gene sequencing. Bio edit sequence alignment editor software was used to detect the possible mutation, deletion, replacement of nucleotides. Genetic diversity was noticed and genetic variation existing in β-tubulin isotype 1 of the H. contortus population of small ruminants of different regions considered in this study. H. contortus showed three different type of genetic sequences. 75%, 37.5%, 25% and 12.5% of the studied samples showed 100% query cover and identity with isolates and clones of China, UK, Australia and other countries, respectively. Interestingly the neighbor countries such as India and Iran haven’t many similarities with the Pakistani isolates. Thus, it suggests that population density of same genetic makeup H. contortus is scattered worldwide rather than clustering in a single region.

Keywords: Haemonchus contortus, Benzimidazole resistant, β-tubulin-1 gene, abattoirs

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Authors: Sergio Alejandro Cuevas, Catherine Etchebest, Fernando Luis Barroso Da Silva

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The flavivirus genus has several organisms responsible for generating various diseases in humans. Special in Brazil, Zika (ZIKV), Dengue (DENV) and Yellow Fever (YFV) viruses have raised great health concerns due to the high number of cases affecting the area during the last years. Diagnostic is still a difficult issue since the clinical symptoms are highly similar. The understanding of their common structural/dynamical and biomolecular interactions features and differences might suggest alternative strategies towards differential serological diagnostics and therapeutic intervention. Due to their immunogenicity, the primary focus of this study was on the ZIKV, DENV and YFV non-structural proteins 1 (NS1) protein. By means of computational studies, we calculated the main physical chemical properties of this protein from different strains that are directly responsible for the biomolecular interactions and, therefore, can be related to the differential infectivity of the strains. We also mapped the electrostatic differences at both the sequence and structural levels for the strains from Uganda to Brazil that could suggest possible molecular mechanisms for the increase of the virulence of ZIKV. It is interesting to note that despite the small changes in the protein sequence due to the high sequence identity among the studied strains, the electrostatic properties are strongly impacted by the pH which also impact on their biomolecular interactions with partners and, consequently, the molecular viral biology. African and Asian strains are distinguishable. Exploring the interfaces used by NS1 to self-associate in different oligomeric states, and to interact with membranes and the antibody, we could map the strategy used by the ZIKV during its evolutionary process. This indicates possible molecular mechanisms that can explain the different immunological response. By the comparison with the known antibody structure available for the West Nile virus, we demonstrated that the antibody would have difficulties to neutralize the NS1 from the Brazilian strain. The present study also opens up perspectives to computationally design high specificity antibodies.

Keywords: zika, biomolecular interactions, electrostatic interactions, molecular mechanisms

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Authors: Radoslav Stojchevski, Leonid Poretsky, Dimiter Avtanski

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Proinflammatory cytokines play an important role in cancer initiation and progression by mediating the intracellular communication between the cancer cells and tumor microenvironment. Increased tumor growth causing reduced oxygen concentration and oxygen pressure commonly result in hypoxia. Mechanistically, hypoxia is characterized by stabilization and nuclear translocation of hypoxia-inducible factor 1 alpha (HIF-1α) followed by propagation of molecular pathway cascade involving multiple downstream targets. Cobalt(II) chloride (CoCl₂) is commonly used to mimic hypoxia in experimental conditions since it directly induces the expression of HIF-1α. The aim of the present study was to investigate the in vitro effects and the molecular mechanisms by which hypoxia regulates the cytokine secretory profile of breast cancer cells. As a model for this study, we used several breast cancer cell lines bearing various molecular characteristics and metastatic potential (MDA-MB-231 (clauding low, ER-/PR-/HER²⁻), MCF-7 (luminal A, ER⁺/PR⁺/HER²⁻), and BT-474 (liminal B, ER⁺/PR⁺/HER²⁺)). We demonstrated that breast cancer cells secrete numerous cytokines and cytokine ligands, including interleukins, chemokines, and growth factors. Treatment with CoCl₂significantly modulated the breast cancer cells' cytokine expression in a concentration- and time-dependent manner. These effects were mediated via activation of several signaling pathways (JNK/SAPK1, NF-κB, STAT5A/B, and Erk/MAPK1/2). Taken together, the present data define some of the molecular mechanisms by which hypoxia affects the breast cancer cells' cytokine secretory profile, thus contributing to the development of novel therapies for metastatic breast cancer.

Keywords: breast cancer, cytokines, cobalt(II) chloride (CoCl₂), hypoxia

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Authors: Azza T. Tahera, Eman M. Ahmeda, Nadia A. Khalila, Yassin M. Nissanb

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New 3-(pyridin-4-yl)-[1,2,4] triazolo [4,3-b] pyridazine derivatives 2a-i, 4a,b and 6a,b were designed, synthesized and evaluated as cytotoxic agents. All compounds were investigated for their in vitro cytotoxicity at a single dose 10-5M concentration towards 60 cancer cell lines according to USA NCI protocol. The preliminary screening results showed that the majority of tested compounds exhibited remarkable activity against SR (leukemia) cell panel. Molecular docking for all synthesized compounds was performed on the active site of c-Met kinase. The most active compounds, 2f and 4a were further evaluated at a seven dose level screening and their IC50 as a c-Met kinase inhibitors were determined in vitro.

Keywords: triazolopyridazines, pyridazines, cytotoxic activity, cell panel

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Authors: Pyar S. Jassal, Sonal Gupta, Neema Chand, Rajni Johar

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In present study, Low molecular weight chitosan naoparticles (LMWCNP) were synthesized by using low molecular weight chitosan (LMWC) and sodium tripolyphosphate for the adsorption of anthraquinone dyes from waste water. The ionic-gel technique was used for this purpose. Size of nanoparticles was determined by “Scherrer equation”. The absorbance was carried out with UV-visible spectrophotometer for Acid Green 25 (AG25) and Reactive Blue 4 (RB4) dyes solutions at λmax 644 and λmax 598 nm respectively. The removal of dyes was dependent on the pH and the optimum adsorption was between pH 2 to 9. The extraction of dyes was linearly dependent on temperature. The equilibrium parameters, RL was calculated by using the Langmuir isotherm and shows that adsorption of dyes is favorable on the LMWCNP. The XRD images of LMWC show a crystalline nature whereas LMWCNP is amorphous one. The thermo gravimetric analysis (TGA) shows that LMWCNP thermally more stable than LMWC. As the contact time increases, percentage removal of Acid Green 25 and Reactive Blue 4 dyes also increases. TEM images reveal the size of the LMWCNP were in the range of 45-50 nm. The capacity of AG25 dye on LMWC was 5.23 mg/g, it compared with LMWCNP capacity which was 6.83 mg/g respectively. The capacity of RB4 dye on LMWC was 2.30 mg/g and 2.34 mg/g was on LMWCNP.

Keywords: low molecular weight chitosan nanoparticles, anthraquinone dye, removal efficiency, adsorption isotherm

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Authors: Sudhir Kumar Sharma, Ramesh Jagannathan

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The interaction of organic and inorganic matrices of biological origin resulting in self-assembled structures with unique properties is well established. The development of such self-assembled nanostructures by synthetic and bio-inspired techniques is an established field of active research. Among bio-materials, nacre, a laminar stack of calcium carbonate nanosheets, which are interleaved with organic material, has long been focused research due to its unique mechanical properties. In this paper, we present the development of nacre-like lamellar structures made up of calcium carbonate via a wet chemical route. We used the binding affinity of carboxylate anions and calcium cations using poly (acrylic) acid (PAA) to lead CaCO₃ crystallization. In these experiments, we selected calcium acetate as the precursor molecule along with PAA (Mw ~ 8000 Da). We found that Ca⁺²/COO⁻ ratio provided a tunable control for the morphology and growth of CaCO₃ nanostructures. Drop casting one such formulation on a silicon substrate followed by calcination resulted in co-planner, molecular sheets of CaCO₃, separated by a spacer layer of carbon. The scope of our process could be expanded to produce unit cell thick molecular sheets of other important inorganic materials.

Keywords: self-assembled structures, bio-inspired materials, calcium carbonate, wet chemical route

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Authors: Alireza Jalalvand, Maryam Saleh, Somayeh Behjat Khatouni, Zahra Bahri Najafi, Foroozan Fatahinia, Narges Ismailzadeh, Behrokh Farahmand

Abstract:

Object: In the last two decades, the recent outbreak of Coronavirus (SARS-CoV-2) imposed a global pandemic in the world. Despite the increasing prevalence of the disease, there are no effective drugs to treat it. A suitable and rapid way to afford an effective drug and treat the global pandemic is a computational drug study. This study used molecular docking methods to examine the potential inhibition of over 50 antiviral drugs against three fundamental proteins of SARS-CoV-2. METHODS: Through a literature review, three important proteins (a key protease, RNA-dependent RNA polymerase (RdRp), and spike) were selected as drug targets. Three-dimensional (3D) structures of protease, spike, and RdRP proteins were obtained from the Protein Data Bank. Protein had minimal energy. Over 50 antiviral drugs were considered candidates for protein inhibition and their 3D structures were obtained from drug banks. The Autodock 4.2 software was used to define the molecular docking settings and run the algorithm. RESULTS: Five drugs, including indinavir, lopinavir, saquinavir, nelfinavir, and remdesivir, exhibited the highest inhibitory potency against all three proteins based on the binding energies and drug binding positions deduced from docking and hydrogen-bonding analysis. Conclusions: According to the results, among the drugs mentioned, saquinavir and lopinavir showed the highest inhibitory potency against all three proteins compared to other drugs. It may enter laboratory phase studies as a dual-drug treatment to inhibit SARS-CoV-2.

Keywords: covid-19, drug repositioning, molecular docking, lopinavir, saquinavir

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Authors: Driss Cherqaoui, Nouhaila Ait Lahcen, Ismail Hdoufane, Mehdi Oubahmane, Wissal Liman, Christelle Delaite, Mohammed M. Alanazi

Abstract:

The Ebola virus is a highly contagious and deadly pathogen that causes Ebola virus disease. The Ebola virus glycoprotein (EBOV-GP) is a key factor in viral entry into host cells, making it a critical target for therapeutic intervention. Using a combination of computational approaches, this study focuses on the identification of natural compounds that could serve as potent inhibitors of EBOV-GP. The 3D structure of EBOV-GP was selected, with missing residues modeled, and this structure was minimized and equilibrated. Two large natural compound databases, COCONUT and NPASS, were chosen and filtered based on toxicity risks and Lipinski’s Rule of Five to ensure drug-likeness. Following this, a pharmacophore model, built from 22 reported active inhibitors, was employed to refine the selection of compounds with a focus on structural relevance to known Ebola inhibitors. The filtered compounds were subjected to virtual screening via molecular docking, which identified ten promising candidates (five from each database) with strong binding affinities to EBOV-GP. These compounds were then validated through molecular dynamics simulations to evaluate their binding stability and interactions with the target. The top three compounds from each database were further analyzed using ADMET profiling, confirming their favorable pharmacokinetic properties, stability, and safety. These results suggest that the selected compounds have the potential to inhibit EBOV-GP, offering new avenues for antiviral drug development against the Ebola virus.

Keywords: EBOV-GP, Ebola virus glycoprotein, high-throughput drug screening, molecular docking, molecular dynamics, natural compounds, pharmacophore modeling, virtual screening

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Authors: Chro Kawyan

Abstract:

Endothelin-1 (ET-1), the principal individual from the newfound mammalian endothelin group of organically dynamic peptides, was initially distinguished as a 21 buildup powerful vasoconstrictor peptide in vascular endothelial cells. However, it has since been demonstrated to have a wide range of pharmacological activities in tissues both inside and outside the cardiovascular system. Additionally, peptides that have a striking resemblance to ET-1 have been identified as the primary toxic component of snake venom. In addition, late examinations have proposed that warm blooded creatures, including people, produce three unmistakable individuals from this peptide family, ET-1, ET-2 and ET-J, which might have various profiles of organic action and may follow up on particular subtypes of endothelin receptor. Masashi Yanagisawa and Tomoh Masaki survey the ongoing status of the organic chemistry and sub-atomic science of endothelin.

Keywords: thelin, microbiology, molecular biology, cell

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Authors: G. V. Novikov, V. S. Sivozhelezov, S. S. Kolesnikov, K. V. Shaitan

Abstract:

The study reports about the influence of binding of orthosteric ligands as well as point mutations on the conformational dynamics of β-2-adrenoreceptor. Using molecular dynamics simulation we found that there was a little fraction of active states of the receptor in its apo (ligand free) ensemble corresponded to its constitutive activity. Analysis of MD trajectories indicated that such spontaneous activation of the receptor is accompanied by the motion in intracellular part of its alpha-helices. Thus receptor’s constitutive activity directly results from its conformational dynamics. On the other hand the binding of a full agonist resulted in a significant shift of the initial equilibrium towards its active state. Finally, the binding of the inverse agonist stabilized the receptor in its inactive state. It is likely that the binding of inverse agonists might be a universal way of constitutive activity inhibition in vivo. Our results indicate that ligand binding redistribute pre-existing conformational degrees of freedom (in accordance to the Monod-Wyman-Changeux-Model) of the receptor rather than cause induced fit in it. Therefore, the ensemble of biologically relevant receptor conformations is encoded in its spatial structure, and individual conformations from that ensemble might be used by the cell in conformity with the physiological behaviour.

Keywords: seven-transmembrane receptors, constitutive activity, activation, x-ray crystallography, principal component analysis, molecular dynamics simulation

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Authors: Babak Safaei, A. M. Fattahi

Abstract:

In the present study we have investigated axial buckling characteristics of nanocomposite beams reinforced by single-walled carbon nanotubes (SWCNTs). Various types of beam theories including Euler-Bernoulli beam theory, Timoshenko beam theory and Reddy beam theory were used to analyze the buckling behavior of carbon nanotube-reinforced composite beams. Generalized differential quadrature (GDQ) method was utilized to discretize the governing differential equations along with four commonly used boundary conditions. The material properties of the nanocomposite beams were obtained using molecular dynamic (MD) simulation corresponding to both short-(10,10) SWCNT and long-(10,10) SWCNT composites which were embedded by amorphous polyethylene matrix. Then the results obtained directly from MD simulations were matched with those calculated by the mixture rule to extract appropriate values of carbon nanotube efficiency parameters accounting for the scale-dependent material properties. The selected numerical results were presented to indicate the influences of nanotube volume fractions and end supports on the critical axial buckling loads of nanocomposite beams relevant to long- and short-nanotube composites.

Keywords: nanocomposites, molecular dynamics simulation, axial buckling, generalized differential quadrature (GDQ)

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Authors: Paromik Bhattacharyya, Vijay Kumar, Johannes Van Staden

Abstract:

Micropropagation is an important tool for the conservation of threatened and commercially important plant species of which orchids deserve special attention. Ansellia africana is one such medicinally important orchid species having much commercial significance. Thus, development of regeneration protocols for producing clonally stable regenerates using axillary buds is of much importance. However, for large-scale micropropagation to become not only successful but also acceptable by end-users, somaclonal variations occurring in the plantlets need to be eliminated. In the light of the various factors (genotype, ploidy level, in vitro culture age, explant and culture type, etc.) that may account for the somaclonal variations of divergent genetic changes at the cellular and molecular levels, genetic analysis of micropropagated plants using a multidisciplinary approach is of utmost importance. In the present study, the clonal integrity of the long term micropropagated A. africana plants were assessed using advanced molecular marker system i.e. Start Codon Targeted Polymorphism (SCoT). Our studies recorded a clonally stable regeneration protocol for A. africana with a very high degree of clonal fidelity amongst the regenerates. The results obtained from these molecular analyses could help in modifying the regeneration protocols for obtaining clonally stable true to type plantlets for sustainable commercial use.

Keywords: medicinal orchid micropropagation, start codon targeted polymorphism (SCoT), RAP), traditional African pharmacopoeia, genetic fidelity

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Authors: Mariam Mojally, Randa Abdou, Wisal Bokhari, Sultan Sab, Mohammed Dawoud, Amjad Albohy

Abstract:

Secondary metabolites produced by endophytes are an excellent source of biologically active compounds. In our current study, we evaluated terezine E and 14-hydroxyterezine D for binding to the active site of histone deacetylase (PDB ID: 4CBT) and matrix metalloproteinase 9 (PDB ID: 4H3X) by molecular docking using AutoDock Vina software after having tested their cytotoxic activities on three cell lines (human ductal breast epithelial tumor cells (T47D)-HCC1937), human hepatocarcinoma cell line (HepG2)-HB8065), and human colorectal carcinoma cells (HCT-116)-TCP1006, purchased from ATCC, USA)). Additionally, their antimicrobial activities were investigated, and their minimum inhibitory concentration (MIC) values were determined against P. notatum and S. aureus by the broth microdilution method. Higher cytotoxicity was observed for terezine E against all tested cell lines compared to 14-hydroxyterezine D. Molecular docking results supported the high cytotoxicity of terezine E and showed higher binding affinity with 4CBT with an energy score of 9 kcal/mol. Terezine E showed higher antibacterial and antifungal activities than 14-hydroxyrerezine D: MIC values were 15.45 and 21.73 mg/mL against S. aureus and 8.61 and 11.54 mg/mL against P. notatum, respectively

Keywords: Terezine E, 14-Hydroxyterezine D, cytotoxicity, antimicrobial activity, molecular docking

Procedia PDF Downloads 75