Search results for: molecular structure

Authors: Jayanthi Sivaraman

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Claudins are the important components of the tight junctions that play a key role in paracellular permeability. Among various members of Claudin family, Claudin 4 (CLDN4) is found to be overexpressed in ovarian, pancreatic carcinomas and other epithelial malignancies. Therefore, in this study, an attempt has been made to identify potent inhibitors for CLDN4 from the ZINC database using virtual screening, molecular docking and molecular dynamics simulations. A well refined molecular model of CLDN4 was built using Prime of Schrodinger v10.2(Template- PDB ID: 4P79). Approximately, 6 million compounds from ZINC database are subjected to high-throughput virtual screening (HTVS) against the active site of CLDN4. Molecular docking using GLIDE predicted ARG31, ASN142, ASP146 and ARG158 as critically important residues. Furthermore, three compounds from ZINC database (ZINC96331839, ZINC36533519 and ZINC75819394) showed highly promising ADME properties and binding affinity with stable conformation. The therapeutic efficiency of these lead compounds is evaluated and confirmed by in-vitro and in-vivo studies which leads to the development of novel anti-cancer drugs.

Keywords: ADME property, inhibitors, molecular docking, virtual screening

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Authors: Jeoungsu Na, Jaehawn Lee, Changil Hong, Suhee Kim

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A molecular dynamics simulation in a converging-diverging nozzle was performed to study molecular collisions and their influence to average flow velocity according to a variety of vacuum levels. The static pressures and the dynamic pressure exerted by the molecule collision on the selected walls were compared to figure out the intensity variances of the directional flows. With pressure differences constant between the entrance and the exit of the nozzle, the numerical experiment was performed for molecular velocities and directional flows. The result shows that the velocities increased at the nozzle exit as the vacuum level gets higher in that area because less molecular collisions.

Keywords: cavitation, molecular collision, nozzle, vacuum, velocity increase

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Authors: Abhishek Kumar Gupta

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Atomistic Molecular Dynamics (MD) Simulations have been performed to study the effect of monovalent salt i.e. NaCl concentration (Cs) and chain degree of neutralization (f) on the structure and dynamics of anionic poly(methacrylic acid) (PMA) in dilute aqueous solutions. In the present study, the attention is to unveil the conformational structure, hydrogen-bonding, local polyion-counterion structure, h-bond dynamics, chain dynamics and thermodynamic enthalpy of solvation of a-PMA in dilute aqueous solutions as a function of salt concentration, Cs and f. The results have revealed that at low salt concentration, the conformational radius of gyration (Rg) increases and then decreases reaching a maximum in agreement with the reported light scattering experimental results. The Rg at f = 1 shows a continual decrease and acquire a plateau value at higher salt concentration in agreement with results obtained by light scattering experiments. The radial distribution functions between PMA, salt and water atoms has been computed with respect to atom and centre-of-mass to understand the intermolecular structure in detail. The results pertaining to PMA chain conformations and hydrogen bond autocorrelation function showcasing the h-bond dynamics will be presented. The results pertaining to chain dynamics will be presented. The results pertaining to counterion condensation on the PMA chain shows greater condensation of Na+ ions on to the carboxylate ions with increase in salt concentration. Moreover, the solvation enthalpy of the system as a function of salt concentration will be presented.

Keywords: conformations, molecular dynamics simulations, NaCl concentration, radial distribution functions

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Authors: Muchun Yu, Xue Gao, Qian Chen

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As a novel passive vibration isolation technology, molecular spring isolator (MSI) is investigated in this paper. An MSI consists of water and hydrophobic zeolites as working medium. Under periodic excitation, water molecules intrude into hydrophobic pores of zeolites when the pressure rises and water molecules extrude from hydrophobic pores when pressure drops. At the same time, energy is stored, released and dissipated. An MSI of piston-cylinder structure was designed in this work. Experiments were conducted to investigate the stiffness properties of MSI. The results show that MSI exhibits high-static-low dynamic (HSLD) stiffness. Furthermore, factors such as the quantity of zeolites, temperature, and ions in water are proved to have an influence on the stiffness properties of MSI.

Keywords: hydrophobic zeolites, molecular spring, stiffness, vibration isolation

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Authors: Ling Dai

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Surface-sensing devices such as atomic force microscope have been widely used to characterize the surface structure and properties of nanoscale polymer films. However, using molecular dynamics simulations, we show that there is intrinsic and unavoidable inelastic deformation at polymer surfaces induced by the sensing tip. For linear chain polymers like perfluoropolyether, such tip-induced deformation derives from the differences in the atomic interactions which are atomic specie-based Van der Waals interactions, and resulting in atomic shuffling and causing inelastic alternation in both molecular structures and mechanical properties at the regions of the polymer surface. For those aromatic chain polymers like epoxy, the intrinsic deformation is depicted as the intra-chain rotation of aromatic rings and kinking of linear atomic connections. The present work highlights the need to reinterpret the data obtained from surface-sensing tests by considering this intrinsic inelastic deformation occurring at polymer surfaces.

Keywords: polymer, surface, nano, molecular dynamics

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Authors: Lidija R. Jevrić, Sanja O. Podunavac-Kuzmanović, Strahinja Z. Kovačević

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Quantitative structure-retention relationship (QSRR) analysis was used to predict the chromatographic behavior of s-triazine derivatives by using theoretical descriptors computed from the chemical structure. Fundamental basis of the reported investigation is to relate molecular topological descriptors with chromatographic behavior of s-triazine derivatives obtained by reversed-phase (RP) thin layer chromatography (TLC) on silica gel impregnated with paraffin oil and applied ethanol-water (φ = 0.5-0.8; v/v). Retention parameter (RM0) of 14 investigated s-triazine derivatives was used as dependent variable while simple connectivity index different orders were used as independent variables. The best QSRR model for predicting RM0 value was obtained with simple third order connectivity index (3χ) in the second-degree polynomial equation. Numerical values of the correlation coefficient (r=0.915), Fisher's value (F=28.34) and root mean square error (RMSE = 0.36) indicate that model is statistically significant. In order to test the predictive power of the QSRR model leave-one-out cross-validation technique has been applied. The parameters of the internal cross-validation analysis (r2CV=0.79, r2adj=0.81, PRESS=1.89) reflect the high predictive ability of the generated model and it confirms that can be used to predict RM0 value. Multivariate classification technique, hierarchical cluster analysis (HCA), has been applied in order to group molecules according to their molecular connectivity indices. HCA is a descriptive statistical method and it is the most frequently used for important area of data processing such is classification. The HCA performed on simple molecular connectivity indices obtained from the 2D structure of investigated s-triazine compounds resulted in two main clusters in which compounds molecules were grouped according to the number of atoms in the molecule. This is in agreement with the fact that these descriptors were calculated on the basis of the number of atoms in the molecule of the investigated s-triazine derivatives.

Keywords: s-triazines, QSRR, chemometrics, chromatography, molecular descriptors

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Authors: Strahinja Kovačević, Sanja Podunavac-Kuzmanović, Lidija Jevrić, Milica Karadžić

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The present study is based on the quantitative structure-activity relationship (QSAR) analysis of eighteen compounds with anti-prion activity. The structures and anti-prion activities (expressed in response units, RU%) of the analyzed compounds are taken from CHEMBL database. In the first step of analysis 85 molecular descriptors were calculated and based on them the hierarchical cluster analysis (HCA) and principal component analysis (PCA) were carried out in order to detect potential significant similarities or dissimilarities among the studied compounds. The calculated molecular descriptors were physicochemical, lipophilicity and ADMET (absorption, distribution, metabolism, excretion and toxicity) descriptors. The first stage of the QSAR analysis was simple linear regression modeling. It resulted in one acceptable model that correlates Henry's law constant with RU% units. The obtained 2D-QSAR model was validated by cross-validation as an internal validation method. The validation procedure confirmed the model’s quality and therefore it can be used for prediction of anti-prion activity. The next stage of the analysis of anti-prion activity will include 3D-QSAR and molecular docking approaches in order to select the most promising compounds in treatment of prion diseases. These results are the part of the project No. 114-451-268/2016-02 financially supported by the Provincial Secretariat for Science and Technological Development of AP Vojvodina.

Keywords: anti-prion activity, chemometrics, molecular modeling, QSAR

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Authors: Nikhil Agrawal, Adam A. Skelton

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

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

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Authors: Kaining Zhang, Lang Chen, Danyang Liu, Jianying Lu, Kun Yang, Junying Wu

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In order to solve the problem of a large amount of simulation and limited simulation scale in the first-principle molecular dynamics simulation of energetic material detonation reaction, we established an artificial intelligence model for analyzing and predicting the detonation reaction mechanism of CL-20 based on the first-principle molecular dynamics simulation of the multiscale shock technique (MSST). We employed principal component analysis to identify the dominant charge features governing molecular reactions. We adopted the K-means clustering algorithm to cluster the reaction paths and screen out the key reactions. We introduced the neural network algorithm to construct the mapping relationship between the charge characteristics of the molecular structure and the key reaction characteristics so as to establish a calculation method for predicting detonation reactions based on the charge characteristics of CL-20 and realize the rapid analysis of the reaction mechanism of energetic materials.

Keywords: energetic material detonation reaction, first-principle molecular dynamics simulation of multiscale shock technique, neural network, CL-20

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Authors: Temnov D., Volgina E., Gerasimov D.

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Relaxation processes in polyvinylidene fluoride (PVDF) films were studied by the method of thermally stimulated fractional polarization currents (TSTF). The films were obtained by extrusion of a polymer melt followed by isometric annealing. PVDF granules of the Kynar-720 brand (Atofina Chemicals, USA) with a molecular weight of Mw=190,000 g•mol-1 were used for the manufacture of films. The annealing temperature was varied in the range from 120 °C to 170 °C in increments of 10 °C. The dependences of the degree of crystallinity of films (χ) and the intensity of thermally stimulated depolarization currents on the annealing temperature (Toc) are investigated. The TSTF spectra were obtained at the TSC II facility (Setaram, France). Measurements were carried out in a helium atmosphere, and the values of currents were determined by a Keithley electrometer. The annealed PVDF films were polarized at an electric field strength of 100 V/mm at a temperature of 31°C, after which they were cooled to 26°C, at which they were kept for 1 minute. During depolarization, the external field was removed, and the short-circuit sample was cooled to 0°C. The thermally stimulated short-circuit current was recorded during linear heating. Relaxation processes in PVDF films were studied in the temperature range from 0 – 70 °C. It is shown that the intensity curve of the peaks of TST FP has a course that is the reverse of the dependence of the degree of crystallinity on the annealing temperature. This allows us to conclude that the relaxation processes occurring in PVDF in the 35°C region are associated with the amorphous part of the structure of PVDF films between the layers of the spherulite crystalline phase.

Keywords: molecular and supramolecular structure, thermally stimulated currents, polyvinylidene fluoride films, relaxation processes

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Authors: Adam Abate, Elham Rasti, Philip Romero

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Beta-glucosidase is the key enzyme component present in cellulase and completes the final step during cellulose hydrolysis by converting the cellobiose to glucose. The regulatory properties of beta-glucosidases are most commonly found for the retaining and inverting enzymes. Hydrolysis of a glycoside typically occurs with general acid and general base assistance from two amino acid side chains, normally glutamic or aspartic acids. In order to obtain more detailed information on the dynamic events origination from the interaction with enzyme active site, we carried out molecular dynamics simulations of beta-glycosidase in protonated state (Glu-H178) and deprotonated state (Glu178). The theoretical models generated from our molecular dynamics simulations complement and advance the structural information currently available, leading to a more detailed understanding of Beta-glycosidase structure and function. This article presents the important role of Asn307 in enzyme activity of beta-glucosidase

Keywords: Beta-glucosidase, GROMACS, molecular dynamics simulation, structural parameters

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Authors: Adel Belayadi, Ahmed Mougari, Boualem Bourahla

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Molecular junctions are currently considered a promising style in the miniaturization of electronic devices. In this contribution, we provide a tight-binding model to investigate the quantum transport properties across-molecular junctions sandwiched between 2D-graphene nanoribbons in the zigzag direction. We investigate, in particular, the effect of embedded atoms such as Gold and Silicon across the molecular junction. The results exhibit a resonance behavior in terms of incident Fermi levels, depending on the molecular junction type. Additionally, the transport properties under a perpendicular magnetic field exhibit an oscillation for the transmittance versus the magnetic field strength.

Keywords: molecular junction, 2D-graphene nanoribbons, quantum transport properties, magnetic field

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Authors: R. O. Ocaya, J. J. Terblans

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The laws of Newtonian mechanics allow ab-initio molecular dynamics to model and simulate particle trajectories in material science by defining a differentiable potential function. This paper discusses some considerations for the coding of ab-initio programs for simulation on a standalone computer and illustrates the approach by C language codes in the context of embedded metallic atoms in the face-centred cubic structure. The algorithms use velocity-time integration to determine particle parameter evolution for up to several thousands of particles in a thermodynamical ensemble. Such functions are reusable and can be placed in a redistributable header library file. While there are both commercial and free packages available, their heuristic nature prevents dissection. In addition, developing own codes has the obvious advantage of teaching techniques applicable to new problems.

Keywords: C language, molecular dynamics, simulation, embedded atom method

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Authors: S. Chandrasekaran, S. Nandita, M. Shivathmika, Srikrishnan Shivakumar

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The objective of the research work is to analyze the computational chemical-composition of carbohydrates in the context of healthcare informatics. The computation involves the representation of complex chemical molecular structure of carbohydrate using graph theory and in a deployable Chemical Markup Language (CML). The parallel molecular structure of the chemical molecules with or without other adulterants for the sake of business profit can be analyzed in terms of robustness and derivatization measures. The rural healthcare program should create awareness in malnutrition to reduce ill-effect of decomposition and help the consumers to know the level of such energy storage mixtures in a quantitative way. The earlier works were based on the empirical and wet data which can vary from time to time but cannot be made to reuse the results of mining. The work is carried out on the quantitative computational chemistry on carbohydrates to provide a safe and secure right to food act and its regulations.

Keywords: carbohydrates, chemical-composition, chemical markup, robustness, food safety

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Authors: Fathi Soliman

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With the ultimate goal of developing the separation of n-paraffin as phase change material (PCM) by means of molecular dynamic simulations, we attempt to predict the solubility of aromatic n-paraffin in two organic solvents: Butyl Acetate (BA) and Methyl Iso Butyl Ketone (MIBK). A simple model of aromatic paraffin: 2-hexadecylantharacene with amorphous molecular structure and periodic boundary conditions was constructed. The results showed that MIBK is the best solvent to separate ultra-pure phase change materials and this data was compatible with experimental data done to separate ultra-pure n-paraffin from waste petroleum aromatic paraffin wax, the separated n-paraffin was characterized by XRD, TGA, GC and DSC, moreover; data revealed that the n-paraffin separated by using MIBK is better as PCM than that separated using BA.

Keywords: molecular dynamics simulation, n-paraffin, organic solvents, phase change materials, solvent extraction

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Authors: Elmira Ghanbari, Jan Van Esch, Stephen J. Picken, Sahil Aggarwal

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Low-molecular-weight organogelators form gels by self-assembly into the crystalline network which immobilizes the organic solvent. For single bisamide organogelator systems, the effect of the molecular structure on the molecular interaction and their self-assembly behavior has been explored. The spatial arrangement of bisamide molecules in the gel-state is driven by a combination of hydrogen bonding and Van der Waals interactions. The hydrogen-bonding pattern between the amide groups of bisamide molecules is regulated by the number of methylene spacers; the even number of methylene spacers between two amide groups, in even-spaced bisamides, leads to the antiparallel position of amide groups within a molecule. An even-spaced bisamide molecule with antiparallel amide groups can make two pairs of hydrogen bonding with the molecules on the same plane. The odd-spaced bisamide with a parallel directionality of amide groups can form four independent hydrogen bonds with four other bisamide molecules on different planes. The arrangement of bisamide molecules in the crystalline state and the interaction of these molecules depends on the molecular structure, particularly the parity of the spacer length between the amide groups in the bisamide molecule. In this study, the directionality of amide groups has been exploited as a structural characteristic to affect the arrangement of molecules in the crystalline state and produce different binary bisamide gelators with different degrees of crystallinities. Single odd- and even-spaced single bisamides were synthesized and blended to produce binary bisamide organogelators to be characterized in order to understand the effect of the different directionality of amide groups on the molecular interaction in the crystalline state. The pattern of molecular interactions between these blended molecules, mixing or phase separation, has been monitored via differential scanning calorimetry (DSC) and crystallography techniques; X-ray powder diffraction (XRD) and Small-angle X-ray scattering (SAXS). The formation of lamellar structures for odd- and even-spaced bisamide gelators was confirmed by using SAXS and XRD techniques. DSC results have shown that binary bisamide organogelators with different parity of methylene spacers (odd-even binary blends) have a higher tendency for phase separation compared to the binary bisamides with the same parity (odd-odd or even-even binary blends). Phase separation in binary odd-even bisamides was confirmed by the presence of individual (100) reflections of odd and even lamellar structures. The structural characteristic of bisamide organogelators, the parity of spacer length in binary systems, is a promising tool to control the arrangement of molecules and their crystalline structure.

Keywords: binary bisamide organogelators, crystalline structure, phase separation, self-assembly behavior

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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: Juan Antonio Mondragon Sanchez, Ruben Santamaria

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The DNA G-quadruplex is a four-stranded DNA structure formed by stacked planes of four base paired guanines (G-quartet). Guanine rich DNA sequences appear in many sites of genomic DNA and can potential form G-quadruplexes, such as those occurring at 3'-terminus of the human telomeric DNA. The formation and stabilization of a G-quadruplex by small ligands at the telomeric region can inhibit the telomerase activity. In turn, the ligands can be used to down regulate oncogene expression making G-quadruplex an attractive target for anticancer therapy. Many G-quadruplex ligands have been proposed with a planar core to facilitate the pi–pi stacking and electrostatic interactions with the G-quartets. However, many drug candidates are impossibilitated to discriminate a G-quadruplex from a double helix DNA structure. In this context, it is important to investigate the site topology for the interaction of a G-quadruplex with a ligand. In this work, we determine the free energy surface of a G-quadruplex-ligand to study the binding modes of the G-quadruplex (TG4T) with the daunomycin (DM) drug. The complex TG4T-DM is studied using classical molecular dynamics in combination with metadynamics simulations. The metadynamics simulations permit an enhanced sampling of the conformational space with a modest computational cost and obtain free energy surfaces in terms of the collective variables (CV). The free energy surfaces of TG4T-DM exhibit other local minima, indicating the presence of additional binding modes of daunomycin that are not observed in short MD simulations without the metadynamics approach. The results are compared with similar calculations on a different structure (the mutated mu-G4T-DM where the 5' thymines on TG4T-DM have been deleted). The results should be of help to design new G-quadruplex drugs, and understand the differences in the recognition topology sites of the duplex and quadruplex DNA structures in their interaction with ligands.

Keywords: g-quadruplex, cancer, molecular dynamics, metadynamics

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Authors: Alexander Hudson, Shaogang Gong

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Structure determination is key to understanding protein function at a molecular level. Whilst significant advances have been made in predicting structure and function from amino acid sequence, researchers must still rely on expensive, time-consuming analytical methods to visualise detailed protein conformation. In this study, we demonstrate that it is possible to make accurate (≥80%) predictions of protein class and architecture from structures determined at low (>3A) resolution, using a deep convolutional neural network trained on high-resolution (≤3A) structures represented as 2D matrices. Thus, we provide proof of concept for high-speed, low-cost protein structure classification at low resolution, and a basis for extension to prediction of function. We investigate the impact of the input representation on classification performance, showing that side-chain information may not be necessary for fine-grained structure predictions. Finally, we confirm that high resolution, low-resolution and NMR-determined structures inhabit a common feature space, and thus provide a theoretical foundation for boosting with single-image super-resolution.

Keywords: transfer learning, protein distance maps, protein structure classification, neural networks

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Authors: Ruqaiya Khalil, Saman Usmani, Zaheer Ul-Haq

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The accurate characterization of ligand binding affinity is indispensable for designing molecules with optimized binding affinity. Computational tools help in many directions to predict quantitative correlations between protein-ligand structure and their binding affinities. Molecular dynamics (MD) simulation is a modern state-of-the-art technique to evaluate the underlying basis of ligand-protein interactions by characterizing dynamic and energetic properties during the event. Autoimmune diseases arise from an abnormal immune response of the body against own tissues. The current regimen for the described condition is limited to immune-modulators having compromised pharmacodynamics and pharmacokinetics profiles. One of the key player mediating immunity and tolerance, thus invoking autoimmunity is Interleukin-2; a cytokine influencing the growth of T cells. Molecular dynamics simulation techniques are applied to seek insight into the inhibitory mechanisms of newly synthesized compounds that manifested immunosuppressant potentials during in silico pipeline. In addition to estimation of free energies associated with ligand binding, MD simulation yielded us a great deal of information about ligand-macromolecule interactions to evaluate the pattern of interactions and the molecular basis of inhibition. The present study is a continuum of our efforts to identify interleukin-2 inhibitors of both natural and synthetic origin. Herein, we report molecular dynamics simulation studies of Interluekin-2 complexed with different antagonists previously reported by our group. The study of protein-ligand dynamics enabled us to gain a better understanding of the contribution of different active site residues in ligand binding. The results of the study will be used as the guide to rationalize the fragment based synthesis of drug-like interleukin-2 inhibitors as immune-modulators.

Keywords: immuno-modulators, MD simulation, protein-ligand interaction, structure-based drug design

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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: 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: Hiroyuki Aoki

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The physical properties of polymer materials are dependent on the conformation and molecular motion of a polymer chain. Therefore, the structure and dynamic behavior of the single polymer chain have been the most important concerns in the field of polymer physics. However, it has been impossible to directly observe the conformation of the single polymer chain in a bulk medium. In the current work, the novel techniques to study the conformation and dynamics of a single polymer chain are proposed. Since a fluorescence method is extremely sensitive, the fluorescence microscopy enables the direct detection of a single molecule. However, the structure of the polymer chain as large as 100 nm cannot be resolved by conventional fluorescence methods because of the diffraction limit of light. In order to observe the single chains, we developed the labeling method of polymer materials with a photo-switchable dye and the super-resolution microscopy. The real-space conformational analysis of single polymer chains with the spatial resolution of 15-20 nm was achieved. The super-resolution microscopy enables us to obtain the three-dimensional coordinates; therefore, we succeeded the conformational analysis in three dimensions. The direct observation by the nanometric optical microscopy would reveal the detailed information on the molecular processes in the various polymer systems.

Keywords: polymer materials, single molecule, super-resolution techniques, conformation

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Authors: Diana Larisa Vladoiu, Vasile Ostafe, Adriana Isvoran

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Molecular docking calculations reveal that pesticides provide favorable interactions with the bacterial chitinases. Pesticides interact with both hydrophilic and aromatic residues involved in the active site of the enzymes, their positions partially overlapping the substrate and the inhibitors locations. Molecular docking outcomes, in correlation with experimental literature data, suggest that the pesticides may be degraded or having an inhibitor effect on the activity of these enzymes, depending of the application dose and rate.

Keywords: chitinases, inhibition, molecular docking, pesticides

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Authors: Irlana C. do Mar, Thayna A. Ferreira, Dayane S. Rezende, Bruno A. M. Figueira, José M. R. Mercury

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This work presents a low-cost Mn starting material to synthesis manganese oxide octahedral molecular sieve with Mg²⁺ in the tunnel (Mg-OMS-1), based on the Mn residues from Carajás Mineral Province (Amazon, Brazil). After hydrothermal and cation exchange procedures, the Mn residues transformed to a single phase, Mg-OMS-1. The raw material and the synthesis processes were analyzed by means of X-ray diffraction (XRD), Scanning electron microscopy (SEM) and Infrared spectroscopy (FTIR). The tunnel structure was synthesized hydrothermally at 180 °C for three days without impurities. According to the XRD analysis, the formation of crystalline Mg-OMS-1 was identified through reflections at 9.8º, 12º and 18º (2θ), as well as a thermal stability around 300 ºC. The SEM analysis indicated that the final product presents good crystallinity with a homogeneous size. In addition, an intense and diagnostic FTIR band was identified at 515 cm⁻¹ related to the MnO₆ octahedral stretching vibrations.

Keywords: Mn residues , Octahedral Molecular Sieve, Synthesis, Characterization

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Authors: Lidija R. Jevrić, Sanja O. Podunavac-Kuzmanović, Strahinja Z. Kovačević

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This study considers the selection of the most suitable in silico molecular descriptors that could be used for s-triazine pesticides characterization. Suitable descriptors among topological, geometrical and physicochemical are used for quantitative structure-retention relationships (QSRR) model establishment. Established models were obtained using linear regression (LR) and multiple linear regression (MLR) analysis. In this paper, MLR models were established avoiding multicollinearity among the selected molecular descriptors. Statistical quality of established models was evaluated by standard and cross-validation statistical parameters. For detection of similarity or dissimilarity among investigated s-triazine pesticides and their classification, principal component analysis (PCA) and hierarchical cluster analysis (HCA) were used and gave similar grouping. This study is financially supported by COST action TD1305.

Keywords: chemometrics, classification analysis, molecular descriptors, pesticides, regression analysis

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Authors: Ashish Kumar Agrahari, Amit Kumar

Abstract:

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal blood disorder that manifests with hemolytic anemia, thrombosis, and peripheral blood cytopenias. The disease is caused by the deficiency of two glycosylphosphatidylinositols (GPI)-anchored proteins (CD55 and CD59) in the hemopoietic stem cells. The deficiency of GPI-anchored proteins has been associated with the somatic mutations in phosphatidylinositol glycan class A (PIGA). However, the mutations that do not cause PNH is associated with the multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2). To best of our knowledge, no computational study has been performed to explore the atomistic level impact of PIGA mutations on the structure and dynamics of the protein. In the current work, we are mainly interested to get insights into the molecular mechanism of PIGA mutations. In the initial step, we screened the most pathogenic mutations from the pool of publicly available mutations. Further, to get a better understanding, pathogenic mutations were mapped to the modeled structure and subjected to 50ns molecular dynamics simulation. Our computational study suggests that four mutations are highly vulnerable to altering the structural conformation and stability of the PIGA protein, which illustrates its association with PNH and MCAHS2 phenotype.

Keywords: homology modeling, molecular dynamics simulation, missense mutations PNH, MCAHS2, PIGA

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Authors: Said Belaaouad

Abstract:

This study aimed to explore the quantitative structure-activity relationship (QSAR) of 1,2,4-Triazine-3(2H)-one derivative as a potential anticancer agent against breast cancer. The electronic descriptors were obtained using the Density Functional Theory (DFT) method, and a multiple linear regression techniques was employed to construct the QSAR model. The model exhibited favorable statistical parameters, including R2=0.849, R2adj=0.656, MSE=0.056, R2test=0.710, and Q2cv=0.542, indicating its reliability. Among the descriptors analyzed, absolute electronegativity (χ), total energy (TE), number of hydrogen bond donors (NHD), water solubility (LogS), and shape coefficient (I) were identified as influential factors. Furthermore, leveraging the validated QSAR model, new derivatives of 1,2,4-Triazine-3(2H)-one were designed, and their activity and pharmacokinetic properties were estimated. Subsequently, molecular docking (MD) and molecular dynamics (MD) simulations were employed to assess the binding affinity of the designed molecules. The Tubulin colchicine binding site, which plays a crucial role in cancer treatment, was chosen as the target protein. Through the simulation trajectory spanning 100 ns, the binding affinity was calculated using the MMPBSA script. As a result, fourteen novel Tubulin-colchicine inhibitors with promising pharmacokinetic characteristics were identified. Overall, this study provides valuable insights into the QSAR of 1,2,4-Triazine-3(2H)-one derivative as potential anticancer agent, along with the design of new compounds and their assessment through molecular docking and dynamics simulations targeting the Tubulin-colchicine binding site.

Keywords: QSAR, molecular docking, ADMET, 1, 2, 4-triazin-3(2H)-ones, breast cancer, anticancer, molecular dynamic simulations, MMPBSA calculation

Procedia PDF Downloads 63

Authors: Dmitry Yu. Korulkin, Raissa A. Muzychkina

Abstract:

Currently to treat infectious diseases bioactive substances of plant origin having fewer side effects than synthetic medicines and medicines similar to natural components of a human body by the structure and action, become very important. One of the groups of secondary metabolites of the plants - alkaloids can be related the number of the most promising sources of medicines of plant origin. Currently, the structure of more than 7500 compounds has been identified. Analyzing the scope of research in the field of chemistry, pharmacology and technology of alkaloids, we can make a conclusion about that there is no system approach during the research of relation structure-activity on different groups of these substances. It is connected not only with a complex structure of their molecules, but also with insufficient information on the nature of their effect on organs, tissues and other targets in organism. The purpose of this research was to identify pharmacophore groups in the structure of alkaloids of endemic Polygonum L. plants growing in Kazakhstan responsible for their antiviral action. To isolate alkaloids pharmacopoeian methods were used. Antiviral activity of alkaloids of Polygonum L. plants was researched in the Institute of Microbiology and Virology of the Ministry of Education and Science of the Republic of Kazakhstan. Virus-inhibiting properties of compounds were studies in experiments with ortho- and paramyxoviruses on the model of chick-embryos. Anti-viral properties were determined using ‘screening test’ method designed to neutralization of a virus at the amount of 100EID50 with set concentrations of medicines. The difference of virus titer compared to control group was deemed as the criterion of antiviral action. It has been established that Polygonum L. alkaloids has high antiviral effect to influenza and parainfluenza viruses. The analysis of correlation of the structure and antiviral activity of alkaloids allowed identifying the main pharmacophore groups, among which the most important are glycosidation, the presence of carbonyl and hydroxyl groups, molecular weight and molecular size.

Keywords: alkaloids, antiviral, bioactive substances, isolation, pharmacophore groups, Polygonum L.

Procedia PDF Downloads 418

Authors: Koo-Yeon Kim, Eun-Hye Kim, Tae-Il Son

Abstract:

Epidermal Growth Factor (EGF, Mw=6,045) has been reported to have high efficiency of wound repair and anti-wrinkle effect. However, the half-life of EGF in the body is too short to exert the biological activity effectively when applied in free form. Growth Factors can be stabilized by immobilization with carbohydrates from thermal and proteolytic degradation. Low molecular weight chitosan (LMCS) and its derivate prepared by hydrogen peroxide has high solubility. LM6A6DC was successfully prepared as a reactive carbohydrate for the stabilization of EGF by the reactions of LMCS with alkalization, tosylation, azidation and reduction. The structure of LM6A6DC was confirmed by FT-IR, 1H NMR and elementary analysis. For enhancing the stability of free EGF, EGF was attached with LM6A6DC by using water-soluble carbodiimide. EGF-LM6A6DC conjugates did not show any cytotoxicity on the Normal Human Dermal Fibroblast(NHDF) 3T3 proliferation at least under 100 ㎍/㎖. In the result, it was considered that LM6A6DC is suitable to immobilize of growth factor.

Keywords: epidermal growth factor (EGF), low-molecular-weight chitosan, immobilization

Procedia PDF Downloads 446