scholarly journals Alkaloids as Inhibitors of Malate Synthase from Paracoccidioides spp.: Receptor-Ligand Interaction-Based Virtual Screening and Molecular Docking Studies, Antifungal Activity, and the Adhesion Process

2015 ◽  
Vol 59 (9) ◽  
pp. 5581-5594 ◽  
Author(s):  
Fausto Guimaraes Costa ◽  
Benedito Rodrigues da Silva Neto ◽  
Ricardo Lemes Gonçalves ◽  
Roosevelt Alves da Silva ◽  
Cecília Maria Alves de Oliveira ◽  
...  
Keyword(s):  
3D Structure ◽  
Three Dimensional ◽  
Binding Pocket ◽  
Docking Studies ◽  
Malate Synthase ◽  
Human Pathogens ◽  
Ligand Interaction ◽  
Content Type ◽  
Extracellular Matrix Components ◽  
Paracoccidioides Spp

ABSTRACTParacoccidioidesis the agent of paracoccidioidomycosis. Malate synthase plays a crucial role in the pathogenicity and virulence of various fungi, such as those that are human pathogens. Thus, an inhibitor of this enzyme may be used as a powerful antifungal without side effects in patients once these enzymes are absent in humans. Here, we searched for compounds with inhibitory capacity against the malate synthase ofParacoccidioidesspecies (PbMLS). The three-dimensional (3D) structure ofPbMLS was determined using the I-TASSER server. Compounds were selected from the ZINC database. Based on the mechanism underlying the interaction of the compounds withPbMLS, it was possible to identify β-carboline moiety as a standard key structure. The compounds with β-carboline moiety that are available in our laboratories were investigated. A total of nine alkaloid compounds were selected. The primary mechanisms of interaction of the alkaloid compounds in the binding pocket ofPbMLS were identified and compared with the mechanism of interaction of acetyl coenzyme A (acetyl-CoA). We discovered that the amphipathic nature of the compounds, concomitant with the presence of β-carboline moiety, was crucial for their stability in the binding pocket ofPbMLS. In addition, the importance of a critical balance of the polar and nonpolar contacts of the compounds in this region was observed. Four β-carboline alkaloid compounds showed the ability to inhibit recombinantPbMLS (PbMLSr) activity,Paracoccidioidesspecies growth, and adhesion of the fungus andPbMLSr to the extracellular matrix components. The cytotoxicity of the alkaloids was also evaluated.

Towards further Understanding the Structural Requirements of Combretastatin- like Chalcones as Inhibitors of Microtubule Polymerization

2020 ◽  
Vol 16 (2) ◽  
pp. 155-166
Author(s):  
Naveen Dhingra ◽  
Anand Kar ◽  
Rajesh Sharma
Keyword(s):  
Three Dimensional ◽  
3D Qsar ◽  
Docking Study ◽  
Structure Activity Relationship ◽  
Docking Studies ◽  
Activity Relationship ◽  
Structural Requirement ◽  
Ligand Interaction ◽  
Microtubule Polymerization ◽  
Structure Activity

Background: Microtubules are dynamic filamentous cytoskeletal structures which play several key roles in cell proliferation and trafficking. They are supposed to contribute in the development of important therapeutic targeting tumor cells. Chalcones are important group of natural compounds abundantly found in fruits & vegetables that are known to possess anticancer activity. We have used QSAR and docking studies to understand the structural requirement of chalcones for understanding the mechanism of microtubule polymerization inhibition. Methods: Three dimensional (3D) QSAR (CoMFA and CoMSIA), pharmacophore mapping and molecular docking studies were performed for the generation of structure activity relationship of combretastatin-like chalcones through statistical models and contour maps. Results: Structure activity relationship revealed that substitution of electrostatic, steric and donor groups may enhance the biological activity of compounds as inhibitors of microtubule polymerization. From the docking study, it was clear that compounds bind at the active site of tubulin protein. Conclusion: The given strategies of modelling could be an encouraging way for designing more potent compounds as well as for the elucidation of protein-ligand interaction.

Fabrication of nanocellulose/PEGDA hydrogel by 3D printing

2018 ◽  
Vol 24 (8) ◽  
pp. 1265-1271 ◽  
Author(s):  
Aimin Tang ◽  
Qinwen Wang ◽  
Shan Zhao ◽  
Wangyu Liu
Keyword(s):  
Additive Manufacturing ◽  
3D Printing ◽  
3D Structure ◽  
Three Dimensional ◽  
Aqueous Dispersion ◽  
Compression Modulus ◽  
Content Type ◽  
Precise Control ◽  
Light Curing ◽  
Equilibrium Swelling Ratio

Purpose Nanocellulose is characterised by favourable biocompatibility, degradability, nanostructure effect, high modulus and high tensile strength and has been widely applied in various fields. The current research in the field of new nanocellulose materials mainly focuses on the hydrogel, aerogel and the tissue engineering scaffold. All of these are three-dimensional (3D) porous materials, but conventional manufacturing technology fails to realise precise control. Therefore, the method of preparing structural materials using 3D printing and adopting the nanocellulose as the 3D printing material has been proposed. Then, how to realise 3D printing of nanocellulose is the problem that should be solved. Design/methodology/approach By adding the photosensitive component polyethyleneglycol diacrylate (PEGDA) in the aqueous dispersion system of nanocellulose, the nanocellulose was endowed with photosensitivity. Then, nanocellulose/PEGDA hydrogels were prepared by the additive manufacturing of nanocellulose through light curing. Findings The results showed that the nanocellulose/PEGDA hydrogels had a uniform shape and a controllable structure. The nanocellulose supported the scaffold structure in the hydrogels. Prepared with 1.8 per cent nanocellulose through 40 s of light curing, the nanocellulose/PEGDA hydrogels had a maximum compression modulus of 0.91 MPa. The equilibrium swelling ratio of the nanocellulose/PEGDA hydrogel prepared with 1.8 per cent nanocellulose was 13.56, which increased by 44 per cent compared with that of the PEGDA hydrogel without nanocellulose. Originality/value The paper proposed a method for rapidly prototyping the nanocellulose with expected properties, which provided a theoretical basis and technological reference for the 3D additive manufacturing of nanocellulose 3D structure materials with a controlled accurate architecture.

Drug Development for Target Ribosomal Protein rpL35/uL29 for Repair of LAMB3R635X in Rare Skin Disease Epidermolysis Bullosa

2021 ◽  
pp. 1-16
Author(s):  
Adriana Rathner ◽  
Petr Rathner ◽  
Andreas Friedrich ◽  
Michael Wießner ◽  
Christian Manuel Kitzler ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Ribosomal Protein ◽  
Small Molecules ◽  
Small Molecule ◽  
Epidermolysis Bullosa ◽  
3D Structure ◽  
Docking Studies ◽  
Full Length ◽  
Ligand Interaction ◽  
Molecular Docking Studies

<b><i>Introduction:</i></b> Epidermolysis bullosa (EB) describes a family of rare genetic blistering skin disorders. Various subtypes are clinically and genetically heterogeneous, and a lethal postpartum form of EB is the generalized severe junctional EB (gs-JEB). gs-JEB is mainly caused by premature termination codon (PTC) mutations in the skin anchor protein LAMB3 (laminin subunit beta-3) gene. The ribosome in majority of translational reads of LAMB3PTC mRNA aborts protein synthesis at the PTC signal, with production of a truncated, nonfunctional protein. This leaves an endogenous readthrough mechanism needed for production of functional full-length Lamb3 protein albeit at insufficient levels. Here, we report on the development of drugs targeting ribosomal protein L35 (rpL35), a ribosomal modifier for customized increase in production of full-length Lamb3 protein from a LAMB3PTC mRNA. <b><i>Methods:</i></b> Molecular docking studies were employed to identify small molecules binding to human rpL35. Molecular determinants of small molecule binding to rpL35 were further characterized by titration of the protein with these ligands as monitored by nuclear magnetic resonance (NMR) spectroscopy in solution. Changes in NMR chemical shifts were used to map the docking sites for small molecules onto the 3D structure of the rpL35. <b><i>Results:</i></b> Molecular docking studies identified 2 FDA-approved drugs, atazanavir and artesunate, as candidate small-molecule binders of rpL35. Molecular interaction studies predicted several binding clusters for both compounds scattered throughout the rpL35 structure. NMR titration studies identified the amino acids participating in the ligand interaction. Combining docking predictions for atazanavir and artesunate with rpL35 and NMR analysis of rpL35 ligand interaction, one binding cluster located near the N-terminus of rpL35 was identified. In this region, the nonidentical binding sites for atazanavir and artesunate overlap and are accessible when rpL35 is integrated in its natural ribosomal environment. <b><i>Conclusion:</i></b> Atazanavir and artesunate were identified as candidate compounds binding to ribosomal protein rpL35 and may now be tested for their potential to trigger a rpL35 ribosomal switch to increase production of full-length Lamb3 protein from a LAMB3PTC mRNA for targeted systemic therapy in treating gs-JEB.

Development and characterization of three-dimensional woven fabric for ultra violet protection

2018 ◽  
Vol 30 (4) ◽  
pp. 536-547
Author(s):  
Adeela Nasreen ◽  
Muhammad Umair ◽  
Khubab Shaker ◽  
Syed Talha Ali Hamdani ◽  
Yasir Nawab
Keyword(s):  
3D Structure ◽  
Three Dimensional ◽  
Air Permeability ◽  
Woven Fabrics ◽  
Woven Fabric ◽  
Protection Factor ◽  
Content Type ◽  
Ultraviolet Protection Factor ◽  
Ultraviolet Protection

Purpose The purpose of this paper is to investigate the effect of materials, three dimensional (3D) structure and number of fabric layers on ultraviolet protection factor (UPF), air permeability and thickness of fabrics. Design/methodology/approach Total 24 fabrics samples were developed using two 3D structures and two weft materials. In warp direction cotton (CT) yarn and in weft direction polypropylene (PP) and polyester (PET) were used. Air permeability, thickness and UPF testings were performed and relationship among fabric layers, air permeability, thickness and UPF was developed. Findings UPF and thickness of fabrics increases with number of fabric layers, whereas air permeability decreases with the increase in number of fabric layers. Furthermore, change of multilayer structure from angle interlock to orthogonal interlock having same base weave does not give significant effect on UPF. However, change of material from polyester (PET) to polypropylene (PP) has a dominant effect on UPF. Minimum of three layers of cotton/polyester fabric, without any aid of ultraviolet radiation (UV) resistant coating, are required to achieve good. Cotton/polyester fabrics are more appropriate for outdoor application due to their long-term resistance with sunlight exposure. Originality/value Long-term exposure to UV is detrimental. So, there is need of proper selection of material and fabric to achieve ultraviolet protection. 3D fabrics have yarns in X, Y as well as in Z directions which provide better ultraviolet protection as compared to two dimensional (2D) fabrics. In literature, mostly work was done on ultraviolet protection of 2D fabrics and surface coating of fabrics. There is limited work found on UPF of 3D woven fabrics.

scholarly journals The atomistic level structure for the activated human κ-opioid receptor bound to the full Gi protein and the MP1104 agonist

2020 ◽  
Vol 117 (11) ◽  
pp. 5836-5843 ◽  
Author(s):  
Amirhossein Mafi ◽  
Soo-Kyung Kim ◽  
William A. Goddard
Keyword(s):  
Opioid Receptor ◽  
Level Structure ◽  
Transmembrane Helix ◽  
3D Structure ◽  
Three Dimensional ◽  
Binding Pocket ◽  
Kappa Opioid Receptor ◽  
Important Target ◽  
Gi Protein ◽  
Intracellular Loops

The kappa opioid receptor (κOR) is an important target for pain therapeutics to reduce depression and other harmful side effects of existing medications. The analgesic activity is mediated by κOR signaling through the adenylyl cyclase-inhibitory family of Gi protein. Here, we report the three-dimensional (3D) structure for the active state of human κOR complexed with both heterotrimeric Gi protein and MP1104 agonist. This structure resulted from long molecular dynamics (MD) and metadynamics (metaMD) simulations starting from the 3.1-Å X-ray structure of κOR–MP1104 after replacing the nanobody with the activated Gi protein and from the 3.5-Å cryo-EM structure of μOR–Gi complex after replacing the 168 missing residues. Using MD and metaMD we discovered interactions to the Gi protein with strong anchors to two intracellular loops and transmembrane helix 6 of the κOR. These anchors strengthen the binding, contributing to a contraction in the binding pocket but an expansion in the cytoplasmic region of κOR to accommodate G protein. These remarkable changes in κOR structure reveal that the anchors are essential for activation.

scholarly journals Quercetin Sensitizes Fluconazole-Resistant Candida albicans To Induce Apoptotic Cell Death by Modulating Quorum Sensing

2015 ◽  
Vol 59 (4) ◽  
pp. 2153-2168 ◽  
Author(s):  
B. N. Singh ◽  
D. K. Upreti ◽  
B. R. Singh ◽  
G. Pandey ◽  
S. Verma ◽  
...  
Keyword(s):  
Cell Death ◽  
Candida Albicans ◽  
Quorum Sensing ◽  
Apoptotic Cell ◽  
Hyphal Growth ◽  
Binding Pocket ◽  
Docking Studies ◽  
Apoptotic Cell Death ◽  
Content Type ◽  
Dose Dependent

ABSTRACTQuorum sensing (QS) regulates group behaviors ofCandida albicanssuch as biofilm, hyphal growth, and virulence factors. The sesquiterpene alcohol farnesol, a QS molecule produced byC. albicans, is known to regulate the expression of virulence weapons of this fungus. Fluconazole (FCZ) is a broad-spectrum antifungal drug that is used for the treatment ofC. albicansinfections. While FCZ can be cytotoxic at high concentrations, our results show that at much lower concentrations, quercetin (QC), a dietary flavonoid isolated from an edible lichen (Usnealongissima), can be implemented as a sensitizing agent for FCZ-resistantC. albicansNBC099, enhancing the efficacy of FCZ. QC enhanced FCZ-mediated cell killing of NBC099 and also induced cell death. These experiments indicated that the combined application of both drugs was FCZ dose dependent rather than QC dose dependent. In addition, we found that QC strongly suppressed the production of virulence weapons—biofilm formation, hyphal development, phospholipase, proteinase, esterase, and hemolytic activity. Treatment with QC also increased FCZ-mediated cell death in NBC099 biofilms. Interestingly, we also found that QC enhances the anticandidal activity of FCZ by inducing apoptotic cell death. We have also established that this sensitization is reliant on the farnesol response generated by QC. Molecular docking studies also support this conclusion and suggest that QC can form hydrogen bonds with Gln969, Thr1105, Ser1108, Arg1109, Asn1110, and Gly1061 in the ATP binding pocket of adenylate cyclase. Thus, this QS-mediated combined sensitizer (QC)-anticandidal agent (FCZ) strategy may be a novel way to enhance the efficacy of FCZ-based therapy ofC. albicansinfections.

scholarly journals Elucidation of the Molecular Basis for Arabinoxylan-Debranching Activity of a Thermostable Family GH62 α-l-Arabinofuranosidase from Streptomyces thermoviolaceus

2014 ◽  
Vol 80 (17) ◽  
pp. 5317-5329 ◽  
Author(s):  
Weijun Wang ◽  
Galina Mai-Gisondi ◽  
Peter J. Stogios ◽  
Amrit Kaur ◽  
Xiaohui Xu ◽  
...  
Keyword(s):  
Hydrophobic Interactions ◽  
Complex Structure ◽  
Three Dimensional ◽  
Binding Pocket ◽  
Content Type ◽  
Wheat Arabinoxylan ◽  
Debranching Enzymes ◽  
The Family ◽  
Multiple Binding ◽  
Hydrolysis Of

ABSTRACTXylan-debranching enzymes facilitate the complete hydrolysis of xylan and can be used to alter xylan chemistry. Here, the family GH62 α-l-arabinofuranosidase fromStreptomyces thermoviolaceus(SthAbf62A) was shown to have a half-life of 60 min at 60°C and the ability to cleave α-1,3l-arabinofuranose (l-Araf) from singly substituted xylopyranosyl (Xylp) backbone residues in wheat arabinoxylan; low levels of activity on arabinan as well as 4-nitrophenyl α-l-arabinofuranoside were also detected. After selective removal of α-1,3l-Arafsubstituents from disubstituted Xylpresidues present in wheat arabinoxylan, SthAbf62A could also cleave the remaining α-1,2l-Arafsubstituents, confirming the ability of SthAbf62A to remove α-l-Arafresidues that are (1→2) and (1→3) linked to monosubstituted β-d-Xylpsugars. Three-dimensional structures of SthAbf62A and its complex with xylotetraose andl-arabinose confirmed a five-bladed β-propeller fold and revealed a molecular Velcro in blade V between the β1 and β21 strands, a disulfide bond between Cys27 and Cys297, and a calcium ion coordinated in the central channel of the fold. The enzyme-arabinose complex structure further revealed a narrow and seemingly rigidl-arabinose binding pocket situated at the center of one side of the β propeller, which stabilized the arabinofuranosyl substituent through several hydrogen-bonding and hydrophobic interactions. The predicted catalytic amino acids were oriented toward this binding pocket, and the catalytic essentiality of Asp53 and Glu213 was confirmed by site-specific mutagenesis. Complex structures with xylotetraose revealed a shallow cleft for xylan backbone binding that is open at both ends and comprises multiple binding subsites above and flanking thel-arabinose binding pocket.

scholarly journals Identification of Novel Chemical Entities for Mirk/Dyrk1B Receptor Using Molecular Modeling and Molecular Dynamic Approaches

2021 ◽  
Author(s):  
Ramar Vanajothi ◽  
Sundaresan Bhavaniramya ◽  
Muthu Umadevi ◽  
Rajendran Vijayakumar ◽  
Yaser E. Alqurashi ◽  
...  
Keyword(s):  
Cancer Prevention ◽  
3D Structure ◽  
Three Dimensional ◽  
Binding Pocket ◽  
Dynamics Simulation ◽  
Dimensional Structure ◽  
Major Health Problem ◽  
Antioxidant Genes ◽  
Dual Specificity ◽  
Pharmacokinetic Properties

Abstract Cancer is a major health problem worldwide and one of the leading death-causing diseases. Mirk (Minibrain-related kinase is a member of the dual-specificity tyrosine-phosphorylation-regulated kinase (Dyrk) family that is highly upregulated in various solid tumors and mediates cell survival including lung cancer. Mirk effectively increases the expression of a series of antioxidant genes, which scavenge the reactive oxygen species and stabilize the p27kip1 that maintain the viability of the quiescent cancer cell and also mediates the cell cycle and survival of cancer cells by influencing the MAPK/ERK signaling pathway. Hence, Mirk acts as a novel therapeutic target for cancer prevention. Owing to the unavailability of the three-dimensional structure of Mirk, in the present study, we have modeled the 3D structure of Mirk, based on the crystal structure of Dyrk1a as a template, and subsequently used it as a target for virtual screening and molecular docking against a small molecule database. Based on the visual inspection, four best hits such as Chembridge_ID 7768949, 7771055, 7758866, and 7764195 have high binding affinity, good docking score, and pharmacokinetic properties were shortlisted. Further, the dynamic stability of lead molecules with modeled Mirk/Dyrk1B was evaluated using 10 ns molecular dynamics simulation approach. The four hit molecules exhibited good and stable binding complex in the binding pocket of the target protein. Collectively the finding of this study suggested that the identified molecules may serve as potential effective anti-cancer inhibitors for cancer prevention.

scholarly journals Docking studies in targeting proteins involved in cardiovascular disorders using phytocompounds from Terminalia arjuna

2020 ◽  
Author(s):  
Vikas Kumar ◽  
Nitin Sharma ◽  
Anuradha Sourirajan ◽  
Prem Kumar Khosla ◽  
Kamal Dev
Keyword(s):  
Molecular Docking ◽  
3D Structure ◽  
Three Dimensional ◽  
Data Bank ◽  
Docking Studies ◽  
Terminalia Arjuna ◽  
Structure Based Drug Design ◽  
Lipinski’S Rule ◽  
Protein Ligand Interactions ◽  
Ligand Interactions

AbstractTerminalia arjuna (Roxb.) Wight and Arnot (T. arjuna) commonly known as Arjuna has been known for its cardiotonic nature in heart failure, ischemic, cardiomyopathy, atherosclerosis, myocardium necrosis and also has been used in the treatment of different human disorders such as blood diseases, anaemia and viral diseases. Our focus has been on phytochemicals which do not exhibit any cytotoxicity and have significant cardioprotective activity. Since Protein-Ligand interactions play a key role in structure-based drug design, therefore with the help of molecular docking, we screened 19 phytochemicals present in T. arjuna and investigated their binding affinity against different cardiovascular target proteins. The three-dimensional (3D) structure of target cardiovascular proteins were retrieved from Protein Data Bank, and docked with 3D Pubchem structures of 19 phytochemicals using Autodock vina. Molecular docking and drug-likeness studies were made using ADMET properties while Lipinski’s rule of five was performed for the phytochemicals to evaluate their cardio protective activity. Among all selected phytocompounds, arjunic acid, arjungenin, and terminic acid were found to fulfill all ADMET rules, drug likeness, and are less toxic in nature. Our studies, therefore revealed that these three phytochemicals from T. arjuna can be used as promising candidates for developing broad spectrum drugs against cardiovascular diseases.

scholarly journals Streptococcus pyogenesCapsule Promotes Microcolony-Independent Biofilm Formation

2019 ◽  
Vol 201 (18) ◽  
Author(s):  
Artur Matysik ◽  
Kimberly A. Kline
Keyword(s):  
Biofilm Formation ◽  
Group A Streptococcus ◽  
3D Structure ◽  
Three Dimensional ◽  
Health Impact ◽  
Bacterial Cells ◽  
Proliferating Cells ◽  
Content Type ◽  
Initial Adhesion ◽  
Wide Range

ABSTRACTBiofilms play an important role in the pathogenesis of group A streptococcus (GAS), a Gram-positive pathogen responsible for a wide range of infections and with a significant public health impact. Although most GAS serotypes are able to form biofilms, there is a large amount of heterogeneity between individual strains in biofilm formation, as measured by standard crystal violet assays. It is generally accepted that biofilm formation includes the initial adhesion of bacterial cells to a surface followed by microcolony formation, biofilm maturation, and extensive production of extracellular matrix that links together proliferating cells and provides a scaffold for the three-dimensional (3D) biofilm structure. However, our studies show that for GAS strain JS95, microcolony formation is not an essential step in static biofilm formation, and instead, biofilm can be effectively formed from slow-growing or nonreplicating late-exponential- or early-stationary-phase planktonic cells via sedimentation and fixation of GAS chains. In addition, we show that the GAS capsule specifically contributes to the alternative sedimentation-initiated biofilms. Microcolony-independent sedimentation biofilms are similar in morphology and 3D structure to biofilms initiated by actively dividing planktonic bacteria. We conclude that GAS can form biofilms by an alternate noncanonical mechanism that does not require transition from microcolony formation to biofilm maturation and which may be obscured by biofilm phenotypes that arise via the classical biofilm maturation processes.IMPORTANCEThe static biofilm assay is a common tool for easy biomass quantification of biofilm-forming bacteria. However,Streptococcus pyogenesbiofilm formation as measured by the static assay is strain dependent and yields heterogeneous results for different strains of the same serotype. In this study, we show that two independent mechanisms, for which the protective capsule contributes opposing functions, may contribute to static biofilm formation. We propose that separation of these mechanisms for biofilm formation might uncover previously unappreciated biofilm phenotypes that may otherwise be masked in the classic static assay.

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