1,720,979 research outputs found
Molecular dynamics study on the conformation stability of laminaran oligomers in various solvents
No full textRational design of inhibitors for drug-resistant HIV-1 aspartic protease mutants
No full textThis report describes a method for the assessment of inhibitor binding affinities to wild type HIV-1 aspartic protease and to its drug-resistant mutant forms. We have elaborated a refined method for molecular modeling of the 3D structures of mutant enzymes and enzyme-inhibitor complexes based on the crystal structure of the wild type form, which employs a full thermodynamic cycle. Model complexes of four HIV-1 aspartic protease mutants with ten analogs of the A77003 inhibitor were considered. Predictions of inhibition efficiency, resistance potential, and hydrophilicity of the redesigned A77003 analogs were obtained by employing molecular mechanics for the evaluation of enzyme-inhibitor complexation energy and the polarizable continuum model for the estimation of solvent effects. Simple qualitative indicators for structural modifications aimed at overcoming the emergence of HIV resistance to protease inhibitors and at increasing the bioavailability of pseudopeptide inhibitors are examined. A semi-quantitative method for the description of enzyme-ligand binding and its implications for the rational design of inhibitors with higher binding affinity towards emerging HIV PR mutants is presented
DESIGN OF PEPTIDOMIMETIC INHIBITORS OF ASPARTIC PROTEASE OF HIV-1 CONTAINING -PHEpsiPRO- CORE AND DISPLAYING FAVOURABLE ADME-RELATED PROPERTIES
No full textAspartic protease (PR) of HIV-1 virus represents a valid therapeutic target for the design of antiviral
agents suitable for treatment of AIDS.We have designed peptidomimetic PR inhibitors containing a novel
dihydroxyethylenediamine –Phe-C[CHOH–CHOH]-Pro– core using molecular modelling approach that
predicts the inhibitory potencies (ICpre
50 ) in terms of computed relative enzyme–inhibitor complexation
Gibbs free energies (DDGcomp). The modelling approach considers not only the enzyme–inhibitor
interactions, but includes also the solvent and entropic effects affecting the enzyme inhibition. The
objectives of this study were to optimize the number and type of flanking residues that occupy the S3, S2
and S20, S30 positions in the PR binding pocket and to select potent lead candidates, which display also
favourable ADME-related properties. The structure-based designwas combined with a synthetic strategy
used to prepare a training set of 10 analogues sharing the –PheCPro– core. This strategy couples
stereochemical control with full flexibility in the choice of the flanking residues and in vitro activity
assays. A QSAR model correlating calculated DDGcomp with the measured ICexp
50 values for the training set
was prepared and confirmed that our computational approach can serve for reliable prediction of PR
inhibitory potencies of peptidomimetics. The appropriate choice of the flanking residues allowed us to
design virtual lead compounds, such as FP14, FP23 and FP76, with reduced molecular weight, predicted
inhibitory potencies in the picomolar range, promising ADME profiles and a potential to escape drug
resistance due to favourable interactions with the PR backbone
Molecular interactions and inclusion phenomena in substituted betacyclodextrins. simple inclusion probes: H2O, C,CH4,NH4+,Hcoo-
No full text
Adhesion of fibroblast cells on thin films representing surfaces of polymeric scaffolds of human urethra rationalized by molecular models of integrin binding: cell adhesion on polymeric scaffolds for regenerative medicine
No full textThis work combines experimental and computational study of Balb/3T3 clone A31 mouse embryo fibroblasts cell line adhesion and proliferation on fourteen different polymeric surfaces prepared from poly(dioxanone) (PDO), poly(glycolic acid) (PGA), poly(hydroxybutyrate) (PHB), and poly(L-lactic acid) (PLA), and their 1:1 mixtures. The study was done with the aim to explore the attractive interactions between various synthetic biomaterials and simple model of the cell attachment mechanism involving the trans-membrane protein integrin. The considered polymeric biodegradable biomaterials can be used as scaffolds for tissue engineering and regenerative urology. During the growth of new tissue, the polymer scaffold is replaced by the extracellular matrix (ECM) synthetized by the proliferating cells. The adhesion and proliferation experiments were done on thin polymer films produced by solvent casting. The computational approach used 3D molecular models of two layers of ordered parallel polymeric fibres, which formed quasi-planar nanosized models of the scaffold surface. Experimental data showed that PGA based polymer films promote the cell adhesion. Cell proliferation testing, performed by incubating the fibroblast cells with the studied polymer films, disclosed that PLA, PHB/PLA and PHB/PGA systems are able to support proliferation of Balb/3T3 clone A31 cells equal to the plain glass. Relative interaction energies between 3D models of polymeric films and the α2 I domain of the cell adhesion receptor integrin α2β1 computed by molecular mechanics suggest that plain polymers PGA, PDO and mixtures PDO/PGA, PHB/PGA, and especially PGA/PLA display elevated affinity to the cell-attachment protein, which confirms the experimental observations. The combination of experimental and modelling approach can assist rational design of synthetic polymeric biomaterial for scaffolds of artificial human urethra that can be efficiently colonized by cells
Structure Based Design of Inhibitors of Aspartic Protease of HIV-1
No full textThe aspartic protease of HIV-1 represents a valid therapeutic target of antiviral agents suitable for the treatment of AIDS. We have designed peptidomimetic inhibitors for this enzyme with a hydroxyethylenediamine core, based on a molecular modeling approach that predicts the effectiveness of the designed compounds in terms of computed enzyme-inhibitor complexation Gibbs free energies. This structurebased molecular design was then combined with a synthetic strategy that couples stereochemical control with full flexibility in the choice of the central core side chains and of the flanking residues. A series of peptidomimetic inhibitors was thus assembled from readily available amino acids and carboxylic acids and -Phe-ω[CH2-(r/s)CHOH]-Phe- cores. The IC50 values for these compounds ranged from 3 nM to 80 μM, allowing a QSAR analysis and identification of factors that determine the inhibition potency of the compounds. Predicted ADME-related properties of the inhibitor candidates span a range of pharmacokinetics profiles, which allows selection of a potent and bioavailable lead compound for further development
Epithelial cell adhesion on films mimicking surface of polymeric scaffolds of artificial urethra compared to molecular modeling of integrin binding
Full text linkIn this study, a combined experimental and computational study of long-term human bladder epithelial cell line HBLAK adhesion and proliferation on five different polymeric surfaces, namely hyaluronic acid, amylose, collagen, polyhydroxybutyrate, and polylactic acid, was performed with the goal to understand the nature of the attraction between various surface materials and a simplified model of the cell surface (transmembrane protein integrin). These biodegradable polymers are frequently used as scaffolds for tissue engineering. During formation of the new tissue, the scaffold polymers are gradually replaced by the natural extracellular matrix of the proliferating cells. Cell adhesion and proliferation experiments were carried out employing thin polymer films prepared by solvent casting while for the computational approach three-dimensional molecular models of layers of ordered polymeric fibers were used as quasi-planar nano-sized models of polymeric surface patches. Experimental results indicated a good capability of amylose, polyhydroxybutyrate, and hyaluronic acid polymer films to foster cell adhesion. Proliferation experiment, carried out by incubating cells with the investigated polymer films for 72 h, showed that all the investigated polymers are able to sustain a good proliferation of HBLAK cells almost comparable to plain glass. Computational estimate of molecular mechanic interaction energies between three-dimensional models of polymeric films and the collagen-binding α 2 I domain of the cell adhesion receptor integrin α 2 β 1 confirmed elevated affinity to amylose and polyhydroxybutyrate that is related to higher polarity of function groups on the film surface as documented by the maps of molecular electrostatic potential. This combined experimental and modeling approach can contribute to rational design and surface modifications of polymeric material suitable for forming the scaffolds of human urethra that can be effectively colonized by stem cells
Modellazione molecolare e progettazione di nuovi inibitori della serin proteasi NS3 del virus dell’HCV
No full text- …
