Search results for: molecular epidemiology

Authors: M. Zemouli, K. Amara, M. Elkeurti, Y. Benallou

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We present a theoretical study of the structural, elastic and thermodynamic properties of the zinc-blende AlBi for a wide temperature range. The simulation calculation is performed in the framework of the molecular dynamics method using the three-body Tersoff potential which reproduces provide, with reasonable accuracy, the lattice constants and elastic constants. Our results for the lattice constant, the bulk modulus and cohesive energy are in good agreement with other theoretical available works. Other thermodynamic properties such as the specific heat and the lattice thermal expansion can also be predicted. In addition, this method allows us to check its ability to predict the phase transition of this compound. In particular, the transition pressure to the rock-salt phase is calculated and the results are compared with other available works.

Keywords: aluminium compounds, molecular dynamics simulations, interatomic potential, thermodynamic properties, structural phase transition

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Authors: D. S. Malatesh, K. J. Ananda, C. Ansar Kamran, K. Ganesh Udupa

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Dirofilaria repens is a mosquito-borne filarioid nematode of dogs and other carnivores and accidentally affects humans. D. repens is reported in many countries, including India. Subcutaneous dirofilariosis caused by D. repens is a zoonotic disease, widely distributed throughout Europe, Asia, and Africa, with higher prevalence reported in dogs from Sri Lanka (30-60%), Iran (61%) and Italy (21-25%). Dirofilariasis in dogs was diagnosed by detection of microfilariae in blood. Identification of different Dirofilaria species was done by using molecular methods like polymerase chain reaction (PCR). Even though many researchers reported molecular evidence of D. repens across India, to our best knowledge there is no data available on molecular diagnosis of D. repens in dogs and its zoonotic implication in Karnataka state a southern state in India. The aim of the present study was to identify the Dirofilaria species occurring in dogs from Karnataka, India. Out of 310 samples screened for the presence of microfilariae using traditional diagnostic methods, 99 (31.93%) were positive for the presence of microfilariae. Based on the morphometry, the microfilariae were identified as D. repens. For confirmation of species, the samples were subjected to PCR using pan filarial primers (DIDR-F1, DIDR-R1) for amplification of internal transcribed spacer region 2 (ITS2) of the ribosomal DNA. The PCR product of 484 base pairs on agarose gel was indicative of D. repens. Hence, a single PCR reaction using pan filarial primers can be used to differentiate filarial species found in dogs. The present study confirms that dirofilarial species occurring in dogs from Karnataka is D. repens and further sequencing studies are needed for genotypic characterization of D. repens.

Keywords: Dirofilaria repens, molecular characterization, polymerase chain reaction, Karnataka, India

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Authors: Boda Sreenivas, Lyathakula Ravindranath, Kanugula Srishailam, Byru Venkatram Reddy

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Extensive research into the optimized structure and molecular properties of 3-Flouro-2-methylbenzoicacid(FMB), 3-Chloro-2-methoxybenzoicacid (CMB), and 3-Bromo-2-methylbenzoicacid (BMB) was carried out using FT-IR, FT-Raman and UV-Visible spectra, as well as theoretically using the DFT approach with B3LYPfunctional in conjunction with 6-311++G(d,p) basis set. The optimized structure was determined by evaluating torsional scans about free rotation bonds. Structure parameters, harmonic vibrational frequencies, potential energy distribution(PED), and infrared and Raman intensities were computed. The computational results from the DFT approach, such asFT-IR, FT-Raman, and UV-Visible spectra, were compared with the experimental results and found good agreement. Observed and calculated frequencies agreed with an rms error of 8.42, 6.60, and 6.95 cm-1 for FMB, CMB, and BMB, respectively. Unambiguous vibrational assignments were made for all fundamentals using PED and eigenvectors. The electronic HOMO-LUMO, H-bonding, and strong conjugative interactions across different molecular entities are discussed using experimental and simulated Ultraviolet-Visible spectra. The title molecules' molecular properties such as dipole moment, mean polarizability, and first-order hyperpolarizability, were calculated to study their non-linear optical (NLO) behavior. The chemical reactivity descriptors and mapped electrostatic surface potential (MESP) were also evaluated. Natural bond orbital (NBO) analysis was used to examine the stability of molecules resulting from hyperconjugative interactions and charge delocalization.

Keywords: ftir/raman spectra, DFT, NLO, homo-lumo, NBO, halogenated benzoic acids

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Authors: Mohamed Moussaoui

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A series of thirty-one potential inhibitors targeting the epidermal growth factor receptor kinase (EGFR), derived from quinazoline, underwent 3D-QSAR analysis using CoMFA and CoMSIA methodologies. The training and test sets of quinazoline derivatives were utilized to construct and validate the QSAR models, respectively, with dataset alignment performed using the lowest energy conformer of the most active compound. The best-performing CoMFA and CoMSIA models demonstrated impressive determination coefficients, with R² values of 0.981 and 0.978, respectively, and Leave One Out cross-validation determination coefficients, Q², of 0.645 and 0.729, respectively. Furthermore, external validation using a test set of five compounds yielded predicted determination coefficients, R² test, of 0.929 and 0.909 for CoMFA and CoMSIA, respectively. Building upon these promising results, eighteen new compounds were designed and assessed for drug likeness and ADMET properties through in silico methods. Additionally, molecular docking studies were conducted to elucidate the binding interactions between the selected compounds and the enzyme. Detailed molecular dynamics simulations were performed to analyze the stability, conformational changes, and binding interactions of the quinazoline derivatives with the EGFR kinase. These simulations provided deeper insights into the dynamic behavior of the compounds within the active site. This comprehensive analysis enhances the understanding of quinazoline derivatives as potential anti-cancer agents and provides valuable insights for lead optimization in the early stages of drug discovery, particularly for developing highly potent anticancer therapeutics

Keywords: 3D-QSAR, CoMFA, CoMSIA, ADMET, molecular docking, quinazoline, molecular dynamic, egfr inhibitors, lung cancer, anticancer

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Authors: M. Dehestani, F. Kamali, M. Klantari Pour, L. Zeidabadi-Nejad

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Chemical bonding between polyethylene glycol (PEG) with pharmaceutical proteins called pegylation is one of the most effective methods of improving the pharmacological properties. The covalent attachment of polyethylene glycol (PEG) to proteins will increase their pharmacologic properties. For the formation of a combination of pegylated protein should first be activated PEG and connected to the protein. Interferons(IFNs) are a family of cytokines which show antiviral effects in front of the biological and are responsible for setting safety system. In this study, the nature and properties of the interaction between active positions of IFNs and polyethylene glycol have been investigated using molecular dynamics simulation. The main aspect of this theoretical work focuses on the achievement of valuable data on the reaction pathways of PEG-IFNs and the transition state energy. Our results provide a new perspective on the interactions, chemical properties and reaction pathways between IFNs and PEG.

Keywords: interaction, interferons, molecular dynamics simulation, polyethylene glycol

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Authors: Mahdi Asghari

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The cavitation phenomenon is the formation and production of micro-bubbles and eventually the bursting of the micro-bubbles inside the liquid fluid, which results in localized high pressure and temperature, causing physical and chemical fluid changes. This pressure and temperature are predicted to be 2000 atmospheres and 5000 °C, respectively. As a result of small bubbles bursting from this process, temperature and pressure increase momentarily and locally, so that the intensity and magnitude of these temperatures and pressures provide the energy needed to break the molecular bonds of heavy compounds such as fuel oil. In this paper, we study the theory of cavitation and the methods of cavitation production by acoustic and hydrodynamic methods and the necessary mechanical equipment and reactors for industrial application of the hydrodynamic cavitation method to break down the molecular bonds of the fuel oil and convert it into useful and economical products.

Keywords: Cavitation, Hydrodynamic Cavitation, Cavitation Reactor, Fuel Oil

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Authors: A. Rezaei, M. Huisman, W. Van Paepegem

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Atomic interactions in molecular systems are mainly studied by particle mechanics. Nevertheless, researches have also put on considerable effort to simulate them using continuum methods. In early 2000, simple equivalent finite element models have been developed to study the mechanical properties of carbon nanotubes and graphene in composite materials. Afterward, many researchers have employed similar structural simulation approaches to obtain mechanical properties of nanostructured materials, to simplify interface behavior of fiber-reinforced composites, and to simulate defects in carbon nanotubes or graphene sheets, etc. These structural approaches, however, are limited to small deformations due to complicated local rotational coordinates. This article proposes a method for the finite element simulation of molecular mechanics. For ease in addressing the approach, here it is called Structural Finite Element Molecular Modeling (SFEMM). SFEMM method improves the available structural approaches for large deformations, without using any rotational degrees of freedom. Moreover, the method simulates molecular conformation, which is a big advantage over the previous approaches. Technically, this method uses nonlinear multipoint constraints to simulate kinematics of the atomic multibody interactions. Only truss elements are employed, and the bond potentials are implemented through constitutive material models. Because the equilibrium bond- length, bond angles, and bond-torsion potential energies are intrinsic material parameters, the model is independent of initial strains or stresses. In this paper, the SFEMM method has been implemented in ABAQUS finite element software. The constraints and material behaviors are modeled through two Fortran subroutines. The method is verified for the bond-stretch, bond-angle and bond-torsion of carbon atoms. Furthermore, the capability of the method in the conformation simulation of molecular structures is demonstrated via a case study of a graphene sheet. Briefly, SFEMM builds up a framework that offers more flexible features over the conventional molecular finite element models, serving the structural relaxation modeling and large deformations without incorporating local rotational degrees of freedom. Potentially, the method is a big step towards comprehensive molecular modeling with finite element technique, and thereby concurrently coupling an atomistic domain to a solid continuum domain within a single finite element platform.

Keywords: finite element, large deformation, molecular mechanics, structural method

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Authors: Bakhtishod Matmuratov, Sakhiba Madraximova, Rakhmat Esanov, Alimjan Matchanov

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Studies have been performed to obtain complexes of glycyrrhizic acid and kinetins in a 2:1 ratio. The complex of glycyrrhizic acid and kinetins in a 2:1 ratio was considered evidence of the formation of a molecular complex by determining the molecular masses using chromato-mass spectroscopy and analyzing the IR spectra.

Keywords: monoammonium salt of glycyrrhizic acid, glycyrrhizic acid, supramolecular complex, isomolar series, IR spectroscopy

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Authors: M. Shahina, K. Fakruddin, C. M. Subhan, S. Rangappa

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In this work, two mixtures with equal concentrations of 1) 4ꞌ-(6-(4-(pentylamino) methyl)-3-hydroxyphenoxy) hexyloxy) biphenyl-4-carbonitrile+-4-((4-(hexyloxy) benzylidene) amino) phenyl 4-butoxy benzoate and 2) 4ꞌ - (6-(4-(hexylamino) methyl)-3-hydroxyphenoxy) hexyloxy) biphenyl-4-carbonitrile+-4-((4-(octyloxy) benzylidene) amino) phenyl 4-butoxy benzoate, have been prepared. The transition temperature and optical texture are observed by using thermal microscopy. Density and birefringence studies are carried out on the above liquid crystalline mixtures. Using density and refractive indices data, the molecular polarizabilities are evaluated by using well-known Vuks and Neugebauer models. The molecular polarizability is also evaluated theoretically by Lippincott δ function model. The results reveal that the polarizability values are same in both experimental and theoretical methods.

Keywords: liquid crystals, optical textures, transition temperature, birefringence, polarizability

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Authors: Noureddine Benharkat, Abdelkader Chouaih, Nourdine Boukabcha

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A thiourea derivative compound was synthesized and subjected to structural analysis using single-crystal X-ray diffraction (XRD). The crystallographic data unveiled its crystallization in the P21/c space group within the monoclinic system. Examination of the dihedral angles indicated a notable non-planar structure. To support and interpret these resulats, density functional theory (DFT) calculations were conducted utilizing the B3LYP functional along with a 6–311 G (d, p) basis set. Additionally, to assess the contribution of intermolecular interactions, Hirshfeld surface analysis and 2D fingerprint plots were employed. Various types of interactions, whether weak intramolecular or intermolecular, within a molecule can significantly impact its stability. The distinctive signature of non-covalent interactions can be detected solely through electron density analysis. The NCI-RDG analysis was employed to investigate both repulsive and attractive van der Waals interactions while also calculating the energies associated with intermolecular interactions and their characteristics. Additionally, a molecular docking study was studied to explain the structure-activity relationship, revealing that the title compound exhibited an affinity energy of -6.8 kcal/mol when docked with B-DNA (1BNA).

Keywords: computational chemistry, density functional theory, crystallography, molecular docking, molecular structure, powder x-ray diffraction, single crystal x-ray diffraction

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Authors: Sumit Sharma, Rakesh Chandra, Pramod Kumar, Navin Kumar

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Molecular dynamics (MD) simulation has been used to study the effect of carbon nanofiber (CNF) volume fraction (Vf) and aspect ratio (l/d) on mechanical properties of CNF reinforced polypropylene (PP) composites. Materials Studio 5.5 has been used as a tool for finding the modulus and damping in composites. CNF composition in PP was varied by volume from 0 to 16%. Aspect ratio of CNF was varied from l/d=5 to l/d=100. To the best of the knowledge of the authors, till date there is no study, either experimental or analytical, which predict damping for CNF-PP composites at the nanoscale. Hence, this will be a valuable addition in the area of nanocomposites. Results show that with only 2% addition by volume of CNF in PP, E11 increases 748%. Increase in E22 is very less in comparison to the increase in E11. With increase in CNF aspect ratio (l/d) till l/d=60, the longitudinal loss factor (η11) decreases rapidly. Results of this study have been compared with those available in literature.

Keywords: carbon nanofiber, elasticity, mechanical properties, molecular dynamics

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Authors: Alya Harichane, Abderraouf Achour, Abdelbaki Benmounah

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The main difficulty encountered in the formulation of high-performance concrete (HPC) consists in choosing the most efficient cement-superplasticizer pair allowing to obtain maximum water reduction, good workability of the concrete in the fresh state, and very good mechanical resistance in the hardened state. The aim of this work is to test the efficiency of three polycarboxylate ether-based superplasticizers (PCE) marketed in Algeria with CEMI 52.5 R cement and to study the effect of chemical structure of PCE on zeta potential, rheological and mechanical properties of cement pastes. The property of the polymers in cement was tested by a Malvern Zetasizer 2000 apparatus and VT 550 viscometer. Results showed that the zeta potential and its rheological properties are related to the molecular weight and the density carboxylic of PCE. The PCE with a moderate molecular weight and the highest carboxylic groups had the best dispersion (high value of zeta potential) and lowest viscosity. The effect of the chemical structure of PCEs on mechanical properties is evaluated by the formulation of cement mortar with these PCEs. The result shows that there is a correlation between the zeta potential of polymer and the compressive strength of cement paste.

Keywords: molecular weight, polycarboxylate-ether superplasticizer, rheology, zeta potential

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Authors: Chaudhari S. G., Saxena, S.

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We systematically and quantitatively investigated the effect of glucose as a model of natural molecular crowding agent on the structure and thermodynamics of Watson-Crick base paired three duplexes (named as D1, D2 and D3) of different base compositions and lengths. Structural analyses demonstrated that duplexes (D1 and D2) folded into B-form with different cations in the absence and presence of glucose while duplex (D3) folded into mixed A and B-form. Moreover, we demonstrated that the duplex was more stable in the absence of glucose, and marginally destabilized in its presence because glucose act as a weak structure breaker on the tetrahedral network of water. In the absence of glucose, the values of ΔG°25 for duplex (D1) were -13.56, -13.76, -12.46, and -12.36 kcal/mol, for duplex (D2) were -13.64, -12.93, -12.86, and -12.30 kcal/mol, for duplex (D3) were -10.05, -11.76, -9.91, -9.70 kcal/mol in the presence of Na+, K+, Na+ + Mg++ and K+ + Mg++ respectively. At high concentration of glucose (1:10000), there was increase in ΔG°25 for duplex (D1) -12.47, -12.37, -11.96, -11.55 kcal/mol, for duplex (D2) -12.37, -11.47, -11.98, -11.01 kcal/mol and for duplex (D3) -8.47, -9.17, -9.16, -8.66 kcal/mol. Our results provide the information that structure and stability of DNA duplex depends on the structure of molecular crowding agent present in its close vicinity. In this study, I have taken the hydration of simple sugar as an essential model for understanding interactions between hydrophilic groups and interfacial water molecules and its effect on hydrogen bonded DNA duplexes. On the basis of these relatively simple building blocks I hope to gain some insights for understanding more generally the properties of sugar–water–salt systems with DNA duplexes.

Keywords: natural molecular crowding, DNA Duplex, structure of DNA, bioengineering and life sciences

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Authors: Hyery Kang, Dong-Yeun Koh, Yun-Ho Ahn, Huen Lee

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Terahertz time-domain spectroscopy (THz-TDS) was used to observe the THF clathrate hydrate system with dosage of polyvinylpyrrolidone (PVP) with three different average molecular weights (10,000 g/mol, 40,000 g/mol, 360,000 g/mol). Distinct footprints of phase transition in the THz region (0.4 - 2.2 THz) were analyzed and absorption coefficients and complex refractive indices are obtained and compared in the temperature range of 253 K to 288 K. Along with the optical properties, ring breathing and stretching modes for different molecular weights of PVP in THF hydrate are analyzed by Raman spectroscopy.

Keywords: clathrate hydrate, terahertz, polyvinylpyrrolidone (PVP), THz-TDS, inhibitor

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Authors: R. Pilafkan, M. Kaffash Irzarahimi, S. F. Asbaghian Namin

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The biaxial buckling behavior of single-layered graphene sheets (SLGSs) is studied in the present work. To consider the size-effects in the analysis, Eringen’s nonlocal elasticity equations are incorporated into classical plate theory (CLPT). A Generalized Differential Quadrature Method (GDQM) approach is utilized and numerical solutions for the critical buckling loads are obtained. Then, molecular dynamics (MD) simulations are performed for a series of zigzag SLGSs with different side-lengths and with various boundary conditions, the results of which are matched with those obtained by the nonlocal plate model to numerical the appropriate values of nonlocal parameter relevant to each type of boundary conditions.

Keywords: biaxial buckling, single-layered graphene sheets, nonlocal elasticity, molecular dynamics simulation, classical plate theory

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Authors: Mahdi Golriz

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The aim of this work is to estimate the change in molecular structure of linear low-density polyethylene (LLDPE) during peroxide modification can be detected by a simple rheological method. For this purpose a commercial grade LLDPE (Exxon MobileTM LL4004EL) was reacted with different doses of dicumyl peroxide (DCP). The samples were analyzed by size-exclusion chromatography coupled with a light scattering detector. The dynamic shear oscillatory measurements showed a deviation of the δ-׀G ׀٭curve from that of the linear LLDPE, which can be attributed to the presence of long-chain branching (LCB). By the use of a simple rheological method that utilizes melt rheology, transformations in molecular architecture induced on an originally linear low density polyethylene during the early stages of reactive modification were indicated. Reasonable and consistent estimates are obtained, concerning the degree of LCB, the volume fraction of the various molecular species produced in peroxide modification of LLDPE.

Keywords: linear low-density polyethylene, peroxide modification, long-chain branching, rheological method

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Authors: Soraya Abtouche, Zeyneb Ghoualem, Syrine Daoudi, Lina Ouldmohamed, Xavier Assfeld

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This work reports density functional theory calculations of the optimized geometries, molecular reactivity, energy gap,and thermodynamic properties of the free base (H2P) and their Zn (II) metallated (ZnP), bearing one, two, or three carboxylic acid groups using the hybrid functional B3LYP, Cam-B3lYP, wb97xd with 6-31G(d,p) basis sets. When donating groups are attached to the molecular dye, the bond lengths are slightly decreased, which is important for the easy transfer of an electron from donating to the accepting group. For all dyes, the highest occupied molecular orbital/lowest occupied molecular orbital analysis results in positive outcomes upon electron injection to the semiconductor and subsequent dye regeneration by the electrolyte. The ionization potential increases with increasing conjugation; therefore, the compound dye attached to one carboxylic acid group has the highest ionization potential. The results show higher efficiencies of those sensitized with ZnP. These results have been explained, taking into account the electronic character of the metal ion, which acts as a mediator in the injection step, and, on the other hand, considering the number of anchoring groups to which it binds to the surface of TiO2.

Keywords: DSSC, porphyrin, TD-DFT, electronic properties, donor-acceptor groups

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Authors: Mohamed Moussaoui, Mouna Baassi, Soukayna Baammi, Hatim Soufi, Mohammed Salah, Rachid Daoud, Achraf EL Allali, Mohammed Elalaoui Belghiti, Said Belaaouad

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The present study aims to investigate the quantitative structure-activity relationship (QSAR) of a series of Thiazole derivatives reported as anticancer agents (hepatocellular carcinoma), using principally the electronic descriptors calculated by the density functional theory (DFT) method and by applying the multiple linear regression method. The developed model showed good statistical parameters (R²= 0.725, R²ₐ𝒹ⱼ= 0.653, MSE = 0.060, R²ₜₑₛₜ= 0.827, Q²𝒸ᵥ = 0.536). The energy of the highest occupied molecular orbital (EHOMO) orbital, electronic energy (TE), shape coefficient (I), number of rotatable bonds (NROT), and index of refraction (n) were revealed to be the main descriptors influencing the anti-cancer activity. Additional Thiazole derivatives were then designed and their activities and pharmacokinetic properties were predicted using the validated QSAR model. These designed molecules underwent evaluation through molecular docking (MD) and molecular dynamic (MD) simulations, with binding affinity calculated using the MMPBSA script according to a 100 ns simulation trajectory. This process aimed to study both their affinity and stability towards Cyclin-Dependent Kinase 2 (CDK2), a target protein for cancer disease treatment. The research concluded by identifying four CDK2 inhibitors - A1, A3, A5, and A6 - displaying satisfactory pharmacokinetic properties. MDs results indicated that the designed compound A5 remained stable in the active center of the CDK2 protein, suggesting its potential as an effective inhibitor for the treatment of hepatocellular carcinoma. The findings of this study could contribute significantly to the development of effective CDK2 inhibitors.

Keywords: QSAR, ADMET, Thiazole, anticancer, molecular docking, molecular dynamic simulations, MMPBSA calculation

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Authors: Retno A. Vinarti, Lucy M. Hederman

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This research describes a knowledge model for a system which give personalized alert to users about infectious disease risks in the context of weather, location and time. The knowledge model is based on established epidemiological concepts augmented by information gleaned from infection-related data repositories. The existing disease risk prediction research has more focuses on utilizing raw historical data and yield seasonal patterns of infectious disease risk emergence. This research incorporates both data and epidemiological concepts gathered from Atlas of Human Infectious Disease (AHID) and Centre of Disease Control (CDC) as basic reasoning of infectious disease risk prediction. Using CommonKADS methodology, the disease risk prediction task is an assignment synthetic task, starting from knowledge identification through specification, refinement to implementation. First, knowledge is gathered from AHID primarily from the epidemiology and risk group chapters for each infectious disease. The result of this stage is five major elements (Person, Infectious Disease, Weather, Location and Time) and their properties. At the knowledge specification stage, the initial tree model of each element and detailed relationships are produced. This research also includes a validation step as part of knowledge refinement: on the basis that the best model is formed using the most common features, Frequency-based Selection (FBS) is applied. The portion of the Infectious Disease risk model relating to Person comes out strongest, with Location next, and Weather weaker. For Person attribute, Age is the strongest, Activity and Habits are moderate, and Blood type is weakest. At the Location attribute, General category (e.g. continents, region, country, and island) results much stronger than Specific category (i.e. terrain feature). For Weather attribute, Less Precise category (i.e. season) comes out stronger than Precise category (i.e. exact temperature or humidity interval). However, given that some infectious diseases are significantly more serious than others, a frequency based metric may not be appropriate. Future work will incorporate epidemiological measurements of disease seriousness (e.g. odds ratio, hazard ratio and fatality rate) into the validation metrics. This research is limited to modelling existing knowledge about epidemiology and chain of infection concepts. Further step, verification in knowledge refinement stage, might cause some minor changes on the shape of tree.

Keywords: epidemiology, knowledge modelling, infectious disease, prediction, risk

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Authors: Amir Doustgani

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Melt electrospinning is a safe and simple technique for the production of micro and nanofibers which can be an alternative to conventional solvent electrospinning. The effects of various melt-electrospinning parameters, including molecular weight, electric field strength, flow rate and temperature on the morphology and fiber diameter of polylactic acid were studied. It was shown that molecular weight was the predominant factor in determining the obtainable fiber diameter of the collected fibers. An orthogonal design was used to examine process parameters. Results showed that molecular weight is the most effective parameter on the average fiber diameter of melt electrospun PLA nanofibers and the flow rate has the less important impact. Mean fiber diameter increased by increasing MW and flow rate, but decreased by increasing electric field strength and temperature. MFD of optimized fibers was below 100 nm and the result of software was in good agreement with the experimental condition.

Keywords: fiber formation, processing, spinning, melt blowing

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Authors: Mouna Baassi, Mohamed Moussaoui, Sanchaita Rajkhowa, Hatim Soufi, Said Belaaouad

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The objective of this paper is to address the challenging task of targeting Human Immunodeficiency Virus type 1 Reverse Transcriptase (HIV-1 RT) in the treatment of AIDS. Reverse Transcriptase inhibitors (RTIs) have limitations due to the development of Reverse Transcriptase mutations that lead to treatment resistance. In this study, a combination of statistical analysis and bioinformatics tools was adopted to develop a mathematical model that relates the structure of compounds to their inhibitory activities against HIV-1 Reverse Transcriptase. Our approach was based on a series of compounds recognized for their HIV-1 RT enzymatic inhibitory activities. These compounds were designed via software, with their descriptors computed using multiple tools. The most statistically promising model was chosen, and its domain of application was ascertained. Furthermore, compounds exhibiting comparable biological activity to existing drugs were identified as potential inhibitors of HIV-1 RT. The compounds underwent evaluation based on their chemical absorption, distribution, metabolism, excretion, toxicity properties, and adherence to Lipinski's rule. Molecular docking techniques were employed to examine the interaction between the Reverse Transcriptase (Wild Type and Mutant Type) and the ligands, including a known drug available in the market. Molecular dynamics simulations were also conducted to assess the stability of the RT-ligand complexes. Our results reveal some of the new compounds as promising candidates for effectively inhibiting HIV-1 Reverse Transcriptase, matching the potency of the established drug. This necessitates further experimental validation. This study, beyond its immediate results, provides a methodological foundation for future endeavors aiming to discover and design new inhibitors targeting HIV-1 Reverse Transcriptase.

Keywords: QSAR, ADMET properties, molecular docking, molecular dynamics simulation, reverse transcriptase inhibitors, HIV type 1

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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: Neha Kanodia, M. Kamil

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Properties of mono layers of Pluronic F127 at air/water interface have been investigated by using Langmuir trough method. Pluronic F127 is a triblock copolymer of poly (ethyleneoxide) (PEO groups)– poly (propylene oxide) (PO groups)–poly(ethylene oxide) (PEO groups). Surface pressure versus mean molecular area isotherms is studied. The isotherm of the mono layer showed the characteristics of a pancake-to-brush transition upon compression of the mono layer. The effect of adding surfactant (SDS) to polymer and the effect of increasing loading on polymer was also studied. The effect of repeated compression and expansion cycle (or hysteresis curve) is investigated to know about stability of the film formed. Static elasticity of mono layer gives information about molecular arrangement, phase structure and phase transition.

Keywords: surface-pressure, mean molecular area isotherms, hysteresis, static elasticity

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Authors: Junhong Li, Danni Cheng, Yaxin Luo, Xiaowei Yi, Ke Qiu, Wendu Pang, Minzi Mao, Yufang Rao, Yao Song, Jianjun Ren, Yu Zhao

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Background: The number of multiple cancer patients was increasing, and the impact of prior cancer history on salivary gland cancer patients remains unclear. Methods: Clinical, demographic and pathological information on salivary gland cancer patients were retrospectively collected from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2017, and the characteristics and prognosis between patients with a prior cancer and those without prior caner were compared. Univariate and multivariate cox proportional regression models were used for the analysis of prognosis. A risk score model was established to exam the impact of treatment on patients with a prior cancer in different risk groups. Results: A total of 9098 salivary gland cancer patients were identified, and 1635 of them had a prior cancer history. Salivary gland cancer patients with prior cancer had worse survival compared with those without a prior cancer (p<0.001). Patients with a different type of first cancer had a distinct prognosis (p<0.001), and longer latent time was associated with better survival (p=0.006) in the univariate model, although both became nonsignificant in the multivariate model. Salivary gland cancer patients with a prior cancer were divided into low-risk (n= 321), intermediate-risk (n=223), and high-risk (n=62) groups and the results showed that patients at high risk could benefit from surgery, radiation therapy, and chemotherapy, and those at intermediate risk could benefit from surgery. Conclusion: Prior cancer history had an adverse impact on the survival of salivary gland cancer patients, and individualized treatment should be seriously considered for them.

Keywords: prior cancer history, prognosis, salivary gland cancer, SEER

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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 and pharmacokinetic and toxicological analysis to evaluate their possible inhibitory effect on the cholinesterase enzymes. Two phytoconstituents belonging to cannabinoid derivatives were revealed to be promising candidates for Alzheimer's 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 interaction 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 a spontaneous reaction leading to stable complexes. The conducted investigations have led to great findings that would strongly guide the pharmaceutical industries toward the rational development of potent anti-Alzheimer agents.

Keywords: Alzheimer’s disease, molecular docking, Cannabis sativa L., cholinesterase inhibitors, molecular dynamics, ADMET, MM-PBSA

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Authors: W. P. Hu, J. V. Kumar, Jeffrey J. P. Tsai

Abstract:

The inhibition of SH2 domain regulated protein-protein interactions is an attractive target for developing an effective chemotherapeutic approach in the treatment of disease. Molecular simulation is a useful tool for developing new drugs and for studying molecular recognition. In this study, we searched potential drug compounds for the inhibition of SH2 domain by performing structural similarity search in PubChem Compound Database. A total of 37 compounds were screened from the database, and then we used the LibDock docking program to evaluate the inhibition effect. The best three compounds (AP22408, CID 71463546 and CID 9917321) were chosen for MD simulations after the LibDock docking. Our results show that the compound CID 9917321 can produce a more stable protein-ligand complex compared to other two currently known inhibitors of Src SH2 domain. The compound CID 9917321 may be useful for the inhibition of SH2 domain based on these computational results. Subsequently experiments are needed to verify the effect of compound CID 9917321 on the SH2 domain in the future studies.

Keywords: nonpeptide inhibitor, Src SH2 domain, LibDock, molecular dynamics simulation

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Authors: Rozhgar A. Khailany, Mehri Igci, Emine Bayraktar, Sakip Erturhan, Metin Karakok, Ahmet Arslan

Abstract:

Kidney cancer is the most lethal urological cancer accounting for 3% of adult malignancies. VHL, a tumor-suppressor gene, is best known to be associated with renal cell carcinoma (RCC). The VHL functions as negative regulator of hypoxia inducible factors. Recent sequencing efforts have identified several novel frequent mutations of histone modifying and chromatin remodeling genes in ccRCC (clear cell RCC) including PBRM1 and SETD2. The PBRM1 gene encodes the BAF180 protein, which involved in transcriptional activation and repression of selected genes. SETD2 encodes a histone methyltransferase, which may play a role in suppressing tumor development. In this study, RNAs of 30 paired tumor and normal samples that were grouped according to the types of kidney cancer and clinical characteristics of patients, including gender and average age were examined by RT-PCR, SSCP and sequencing techniques. VHL, PBRM1 and SETD2 expressions were relatively down-regulated. However, statistically no significance was found (Wilcoxon signed rank test, p > 0.05). Interestingly, no mutation was observed on the contrary of previous studies. Understanding the molecular mechanisms involved in the pathogenesis of RCC has aided the development of molecular-targeted drugs for kidney cancer. Further analysis is required to identify the responsible genes rather than VHL, PBRM1 and SETD2 in kidney cancer.

Keywords: kidney cancer, molecular biomarker, expression analysis, mutation screening

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Authors: Alok Shiomurti Tripathi, Ajay Kumar Timiri, Papiya Mitra Mazumder, Anil Chandewar

Abstract:

The present study evaluates the possible drug interaction between glimepiride (GLIM) and sildenafil citrate (SIL) in streptozotocin (STZ) induced in diabetic nephropathic (DN) animals and also postulates the possible mechanism of interaction by molecular modeling studies. Diabetic nephropathy was induced by single dose of STZ (60 mg/kg, ip) and confirms it by assessing the blood and urine biochemical parameters on 28th day of its induction. Selected DN animals were used for the drug interaction between GLIM (0.5mg/kg, p.o.) and SIL (2.5 mg/kg, p.o.) after 29th and 70th day of protocol. Drug interaction were assessed by evaluating the plasma drug concentration using HPLC-UV and also determine the change in the biochemical parameter in blood and urine. Mechanism of the interaction was postulated by molecular modeling study using Maestro module of Schrodinger software. DN was confirmed as there was significant alteration in the blood and urine biochemical parameter in STZ treated groups. The concentration of SIL increased significantly (p<0.001) in rat plasma when co administered with GLIM after 70th day of protocol. Molecular modelling study revealed few important interactions with rat serum albumin and CYP2C9.GLIM has strong hydrophobic interaction with binding site residues of rat serum albumin compared to SIL. Whereas, for CYP2C9, GLIM has strong hydrogen bond with polar contacts and hydrophobic interactions than SIL. Present study concludes that bioavailability of SIL increases when co-administered chronically with GLIM in the management of DN animals and mechanism has been supported by molecular modeling studies.

Keywords: diabetic nephropathy, glimepiride, sildenafil citrate, pharmacokinetics, homology modeling, schrodinger

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Authors: Nahush Modak, Meena Pangarkar, Anand Pathak, Ankita Tamhane

Abstract:

Background: Breast cancer is the prominent cause of cancer and mortality among women. This study was done to show the statistical analysis of a cohort of over 250 patients detected with breast cancer diagnosed by oncologists using Immunohistochemistry (IHC). IHC was performed by using ER; PR; HER2; Ki-67 antibodies. Materials and methods: Formalin fixed Paraffin embedded tissue samples were obtained by surgical manner and standard protocol was followed for fixation, grossing, tissue processing, embedding, cutting and IHC. The Ventana Benchmark XT machine was used for automated IHC of the samples. Antibodies used were supplied by F. Hoffmann-La Roche Ltd. Statistical analysis was performed by using SPSS for windows. Statistical tests performed were chi-squared test and Correlation tests with p<.01. The raw data was collected and provided by National Cancer Insitute, Jamtha, India. Result: Luminal B was the most prevailing molecular subtype of Breast cancer at our institute. Chi squared test of homogeneity was performed to find equality in distribution and Luminal B was the most prevalent molecular subtype. The worse prognostic indicator for breast cancer depends upon expression of Ki-67 and her2 protein in cancerous cells. Our study was done at p <.01 and significant dependence was observed. There exists no dependence of age on molecular subtype of breast cancer. Similarly, age is an independent variable while considering Ki-67 expression. Chi square test performed on Human epidermal growth factor receptor 2 (HER2) statuses of patients and strong dependence was observed in percentage of Ki-67 expression and Her2 (+/-) character which shows that, value of Ki depends upon Her2 expression in cancerous cells (p<.01). Surprisingly, dependence was observed in case of Ki-67 and Pr, at p <.01. This shows that Progesterone receptor proteins (PR) are over-expressed when there is an elevation in expression of Ki-67 protein. Conclusion: We conclude from that Luminal B is the most prevalent molecular subtype at National Cancer Institute, Jamtha, India. There was found no significant correlation between age and Ki-67 expression in any molecular subtype. And no dependence or correlation exists between patients’ age and molecular subtype. We also found that, when the diagnosis is Luminal A, out of the cohort of 257 patients, no patient shows >14% Ki-67 value. Statistically, extremely significant values were observed for dependence of PR+Her2- and PR-Her2+ scores on Ki-67 expression. (p<.01). Her2 is an important prognostic factor in breast cancer. Chi squared test for Her2 and Ki-67 shows that the expression of Ki depends upon Her2 statuses. Moreover, Ki-67 cannot be used as a standalone prognostic factor for determining breast cancer.

Keywords: breast cancer molecular subtypes , correlation, immunohistochemistry, Ki-67 and HR, statistical analysis

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Authors: Rizwan H. Khan, Saima Nusrat

Abstract:

Despite the fact that amyloid associated neurodegenerative diseases and non-neuropathic systemic amyloidosis have allured the research endeavors, as no curative drugs have been proclaimed up till now except for symptomatic cure. Therapeutic compounds which can diminish or disaggregate such toxic oligomers and fibrillar species have been examined and more are on its way. In the present study, we had reported an extensive biophysical, microscopic and computational study, revealing that L-3, 4-dihydroxyphenylalanine (L-Dopa) possess undeniable potency to inhibit heat induced human lysozyme (HL) amyloid fibrillation and also retain the fibril disaggregating potential. L-Dopa interferes in the amyloid fibrillogenesis process by interacting hydrophobically and also by forming hydrogen bonds with the amino acid residues found in amyloid fibril forming prone region of HL as elucidated by molecular docking results. L-Dopa also disaggregates the mature amyloid fibrils into some unorganised species. Thus, L-Dopa and related compounds can work as a promising inhibitor for the therapeutic advancement prospective against systemic amyloidosis.

Keywords: amyloids, disaggregation, human lysozyme, molecular docking

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