Current Issue : July - September Volume : 2014 Issue Number : 3 Articles : 6 Articles
Urokinase-type plasminogen activator (uPA) plays an important role in the regulation of diverse physiologic and pathologic\nprocesses. Experimental research has shown that elevated uPA expression is associated with cancer progression, metastasis, and\nshortened survival in patients, whereas suppression of proteolytic activity of uPA leads to evident decrease of metastasis. Therefore,\nuPA has been considered as a promisingmolecular target for development of anticancer drugs.Thepresent study sets out to develop\nthe new selective uPA inhibitors using computer-aided structural based drug design methods. Investigation involves the following\nstages: computer modeling of the protein active site, development and validation of computer molecular modeling methods:\ndocking (SOL program), postprocessing (DISCORE program), direct generalized docking (FLM program), and the application\nof the quantum chemical calculations (MOPAC package), search of uPA inhibitors among molecules from databases of readymade\ncompounds to find new uPA inhibitors, and design of new chemical structures and their optimization and experimental\nexamination. On the basis of known uPA inhibitors and modeling results, 18 new compounds have been designed, calculated using\nprograms mentioned above, synthesized, and tested in vitro. Eight of them display inhibitory activity and two of them display\nactivity about 10 ??M....
Background: An important mechanism of endocrine activity is chemicals entering target cells via transport\nproteins and then interacting with hormone receptors such as the estrogen receptor (ER). a-Fetoprotein (AFP) is a\nmajor transport protein in rodent serum that can bind and sequester estrogens, thus preventing entry to the\ntarget cell and where they could otherwise induce ER-mediated endocrine activity. Recently, we reported rat AFP\nbinding affinities for a large set of structurally diverse chemicals, including 53 binders and 72 non-binders.\nHowever, the lack of three-dimensional (3D) structures of rat AFP hinders further understanding of the structural\ndependence for binding. Therefore, a 3D structure of rat AFP was built using homology modeling in order to\nelucidate rat AFP-ligand binding modes through docking analyses and molecular dynamics (MD) simulations.\nMethods: Homology modeling was first applied to build a 3D structure of rat AFP. Molecular docking and\nMolecular Mechanics-Generalized Born Surface Area (MM-GBSA) scoring were then used to examine potential rat\nAFP ligand binding modes. MD simulations and free energy calculations were performed to refine models of\nbinding modes.\nResults: A rat AFP tertiary structure was first obtained using homology modeling and MD simulations. The rat AFPligand\nbinding modes of 13 structurally diverse, representative binders were calculated using molecular docking,\n(MM-GBSA) ranking and MD simulations. The key residues for rat AFP-ligand binding were postulated through\nanalyzing the binding modes.\nConclusion: The optimized 3D rat AFP structure and associated ligand binding modes shed light on rat AFP-ligand\nbinding interactions that, in turn, provide a means to estimate binding affinity of unknown chemicals. Our results\nwill assist in the evaluation of the endocrine disruption potential of chemicals....
We have previously isolated several IgG rheumatoid factors (RFs) from patients with both rheumatoid arthritis and idiopathic\nthrombocytopenia purpura using phage display system. To study IgG RFs in patients with other autoimmune diseases, phage display\nantibody libraries froma hepatitisCvirus infected patientwith SjÃ?¨ogrenââ?¬â?¢s syndromewere constructed. After panning, a specific clone\nRFL11 was isolated for characterization in advance.The binding activity and specificity of RFL11 to IgGFc fragmentwere comparable\nto those of RFs previously isolated. The analysis with existed RF-Fc complex structures indicated the homology model of RFL11 is\nsimilar to IgM RF61 complex with high binding affinity of about 6 Ã?â?? 10-8 M. This effect resulted from longer complementaritydetermining\nregion (CDR) combining key somatic mutations. In the RFL11-Fc interfaces, the CDR-H3 loop forms a finger-like\nstructure extending into the bottom of Fc pocket and resulting in strong ion and cation-pi interactions. Moreover, a process of\nantigen-driven maturation was proven by somatically mutated VH residues on H2 and H3 CDR loops in the interfaces. Taken\ntogether, these results suggested that high affinity IgG RFs can be generated in patients with SjÃ?¨ogrenââ?¬â?¢s syndrome andmay play an\nimportant role in the pathogenesis of this autoimmune disease....
The remarkable mechanical strength of cellulose reflects the arrangement of multiple b-1,4-linked glucan chains in a paracrystalline\nfibril. During plant cellulose biosynthesis, a multimeric cellulose synthesis complex (CSC) moves within the plane\nof the plasma membrane as many glucan chains are synthesized from the same end and in close proximity. Many questions\nremain about the mechanism of cellulose fibril assembly, for example must multiple catalytic subunits within one CSC\npolymerize cellulose at the same rate? How does the cellulose fibril bend to align horizontally with the cell wall? Here we\nused mathematical modeling to investigate the interactions between glucan chains immediately after extrusion on the\nplasma membrane surface. Molecular dynamics simulations on groups of six glucans, each originating from a position\napproximating its extrusion site, revealed initial formation of an uncrystallized aggregate of chains from which a protofibril\narose spontaneously through a ratchet mechanism involving hydrogen bonds and van der Waals interactions between\nglucose monomers. Consistent with the predictions from the model, freeze-fracture transmission electron microscopy using\nimproved methods revealed a hemispherical accumulation of material at points of origination of apparent cellulose fibrils\non the external surface of the plasma membrane where rosette-type CSCs were also observed. Together the data support\nthe possibility that a zone of uncrystallized chains on the plasma membrane surface buffers the predicted variable rates of\ncellulose polymerization from multiple catalytic subunits within the CSC and acts as a flexible hinge allowing the horizontal\nalignment of the crystalline cellulose fibrils relative to the cell wall....
The synthesized poly[N,N??-bis(3-silsesquioxanilpropyl)-thiocarbamide] (PSTM-3T) was used and the surface morphology and\nmicrostructure of it were analyzed by scanning electron microscopy with energy dispersive spectrometer (SEM/EDS). The\nmolecular structure change of the PSTM-3T polymer of the PSTM-3T after treatment by acidic solution with different pHs was\nrevealed using FT-IR experiments and ab initio calculations with density functional theory method. The sorption efficiency of the\nheavy metal ions depends on the molecular structure change of PSTM-3T after treatment of different pH aqueous solutions. After\nthe treatment of acidic solution (pH = 2) of PSTM-3T, the polymer formed the tautomer state to increase the sorption efficiency for\nchromate ion. For the increment of pH value for acidic solution, the PSTM-3T polymer was dissociated to increase the sorption\nefficiency for copper ion....
Neurodegenerative disorders are related to the progressive loss of structure or function and, eventually, death of neurons. These\nprocesses are responsible for diseases like Parkinson�s, Alzheimer�s, and Huntington�s, and the main molecular target for the drug\ndesign against these illnesses today is the enzyme acetylcholinesterase (AChE). Following this line, in the present work, we applied\ndocking techniques to study some piperidine derivative inhibitors of AChE and further propose structures of six new AChE\ninhibitors as potential new drugs against neurodegenerative disorders. The best inhibitor proposed was submitted to additional\nmolecular dynamics simulations steps....
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