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Flexible Ligands (flexible + ligand)
Selected AbstractsFacile Synthesis of Flexible Bis(pyrazol-1-yl)alkane and Related Ligands in a Superbasic MediumEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 30 2007Andrei S. Potapov Abstract Flexible ligands 1,3-bis(pyrazol-1-yl)propanes, bis[2-(pyrazol-1-yl)ethyl] ethers, and bis[2-(3,5-dimethylpyrazol-1-yl)ethyl]amine were prepared by a facile procedure involving the reaction of pyrazoles with 1,3-dibromopropane, bis(2-chloroethyl) ether or bis(2-chloroethyl)amine hydrochloride in a superbasic medium (dimethyl sulfoxide/potassium hydroxide). Reaction of bis(2-chloroethyl)amine and pyrazole unexpectedly led to 1,4-bis[2-(pyrazol-1-yl)ethyl]piperazine. The corresponding 4,4,-diiodo-substituted bis(pyrazole) derivatives were prepared by oxidative iodination with I2/HIO3/H2SO4 in acetic acid. Vilsmeier,Haak formylation of some of the prepared compounds yielded the corresponding dialdehydes.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] The role of side chain conformational flexibility in surface recognition by Tenebrio molitor antifreeze proteinPROTEIN SCIENCE, Issue 7 2003Margaret E. Daley AFP, antifreeze protein; DQF-COSY, double quantum filtered correlated spectroscopy; NMR, nuclear magnetic resonance; NOE, nuclear Overhauser enhancement; NOESY, nuclear Overhauser effect spectroscopy; 3J,,, 3-bond scalar coupling constant between spins H, and H, Abstract Two-dimensional nuclear magnetic resonance spectroscopy was used to investigate the flexibility of the threonine side chains in the ,-helical Tenebrio molitor antifreeze protein (TmAFP) at low temperatures. From measurement of the 3J,,1H- 1H scalar coupling constants, the ,1 angles and preferred rotamer populations can be calculated. It was determined that the threonines on the ice-binding face of the protein adopt a preferred rotameric conformation at near freezing temperatures, whereas the threonines not on the ice-binding face sample many rotameric states. This suggests that TmAFP maintains a preformed ice-binding conformation in solution, wherein the rigid array of threonines that form the AFP-ice interface matches the ice crystal lattice. A key factor in binding to the ice surface and inhibition of ice crystal growth appears to be the close surface-to-surface complementarity between the AFP and crystalline ice, and the lack of an entropic penalty associated with freezing out motions in a flexible ligand. [source] SODOCK: Swarm optimization for highly flexible protein,ligand dockingJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 2 2007Hung-Ming Chen Abstract Protein,ligand docking can be formulated as a parameter optimization problem associated with an accurate scoring function, which aims to identify the translation, orientation, and conformation of a docked ligand with the lowest energy. The parameter optimization problem for highly flexible ligands with many rotatable bonds is more difficult than that for less flexible ligands using genetic algorithm (GA)-based approaches, due to the large numbers of parameters and high correlations among these parameters. This investigation presents a novel optimization algorithm SODOCK based on particle swarm optimization (PSO) for solving flexible protein,ligand docking problems. To improve efficiency and robustness of PSO, an efficient local search strategy is incorporated into SODOCK. The implementation of SODOCK adopts the environment and energy function of AutoDock 3.05. Computer simulation results reveal that SODOCK is superior to the Lamarckian genetic algorithm (LGA) of AutoDock, in terms of convergence performance, robustness, and obtained energy, especially for highly flexible ligands. The results also reveal that PSO is more suitable than the conventional GA in dealing with flexible docking problems with high correlations among parameters. This investigation also compared SODOCK with four state-of-the-art docking methods, namely GOLD 1.2, DOCK 4.0, FlexX 1.8, and LGA of AutoDock 3.05. SODOCK obtained the smallest RMSD in 19 of 37 cases. The average 2.29 Å of the 37 RMSD values of SODOCK was better than those of other docking programs, which were all above 3.0 Å. © 2006 Wiley Periodicals, Inc. J Comput Chem 28: 612,623, 2007 [source] Fluctuation analysis and accuracy of a large-scale in silico screenJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 13 2004H. Merlitz Abstract Using a cascadic version of the stochastic tunneling method we perform an all-atom database screen over 186,000 flexible ligands of the NCI 3D database against the thymidine kinase receptor. By analyzing the errors in the binding energy we demonstrate how the cascadic technique is superior to conventional sequential docking techniques and how reliable results for the determination of the top-scoring ligands could be achieved. The substrate corresponding to the crystal structure used in the screen ranks in the upper 0.05% of the database, validating both docking methodology and the applicability of the scoring function to this substrate. Several high ranking ligands of the database display significant structural similarity with known substrates. A detailed analysis of the accuracy of the screening method is carried out, and its dependence on the flexibility of the ligand is quantified. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1568,1575, 2004 [source] Minimum sequence requirements for the binding of paromomycin to the rRNA decoding site ABIOPOLYMERS, Issue 2 2007Peter C. Anderson Abstract We have recently introduced a computational methodology that combines molecular dynamics (MD) simulations, free-energy calculations, and in vitro binding assays to predict the minimum RNA structural requirements for selective, high-affinity RNA binding to small-molecule ligands. Here, we show that this methodology can be applied to the conformationally flexible aminoglycoside antibiotic paromomycin. A RNA consisting of an 11-mer:10-mer duplex that contains one 16S ribosome RNA decoding A-site bound to paromomycin was simulated for 4 ns. The methodology predicts that the 11-mer:10-mer duplex binds to paromomycin with high affinity, whereas smaller RNA duplexes lose complex stability and the ability to bind paromomycin. The predicted high-affinity binding to paromomycin of the 11-mer:10-mer duplex was confirmed experimentally (EC50 = 0.28 ,M), as well as the inability of smaller complexes to bind. Our simulations show good agreement with experiment for dynamic and structural properties of the isolated A-site, including hydrogen-bonding networks and RNA structural rearrangements upon ligand binding. The results suggest that MD simulations can supplement in vitro methods as a tool for predicting minimum RNA-binding motifs for both small, rigid ligands, and large, flexible ligands when structural information is available. © 2007 Wiley Periodicals, Inc. Biopolymers 86: 95,111, 2007. This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [source] Research Article: pso@autodock: A Fast Flexible Molecular Docking Program Based on Swarm IntelligenceCHEMICAL BIOLOGY & DRUG DESIGN, Issue 6 2007Vigneshwaran Namasivayam On the quest of novel therapeutics, molecular docking methods have proven to be valuable tools for screening large libraries of compounds determining the interactions of potential drugs with the target proteins. A widely used docking approach is the simulation of the docking process guided by a binding energy function. On the basis of the molecular docking program autodock, we present pso@autodock as a tool for fast flexible molecular docking. Our novel Particle Swarm Optimization (PSO) algorithms varCPSO and varCPSO-ls are suited for rapid docking of highly flexible ligands. Thus, a ligand with 23 rotatable bonds was successfully docked within as few as 100 000 computing steps (rmsd = 0.87 Å), which corresponds to only 10% of the computing time demanded by autodock. In comparison to other docking techniques as gold 3.0, dock 6.0, flexx 2.2.0, autodock 3.05, and sodock, pso@autodock provides the smallest rmsd values for 12 in 37 protein,ligand complexes. The average rmsd value of 1.4 Å is significantly lower then those obtained with the other docking programs, which are all above 2.0 Å. Thus, pso@autodock is suggested as a highly efficient docking program in terms of speed and quality for flexible peptide,protein docking and virtual screening studies. [source] | ||||||||||