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  • 1
    Electronic Resource
    Electronic Resource
    Computational combinatorial chemistry for de novo ligand design: Review and assessment (1995)
    Springer
    Perspectives in drug discovery and design 3 (1995), S. 51-84 
    Details
    ISSN: 1573-9023
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Computational combinatorial chemistry divides the ligand design problem into three parts: the search for optimal positions and orientations of functional groups in the binding site, the connection of such optimally placed fragments to form candidate ligands, and the estimation of their binding constants. In this review, approaches to each of these problems are described. The present limitations of methodologies are indicated and efforts to improve them are outlined. Applications to HIV-1 aspartic proteinase, which is a target for the development of AIDS therapeutic agents, and human thrombin, a multifunctional enzyme that has a central role in both haemostasis and thrombosis, are presented. The relation between combinatorial methods for drug discovery on the computer and in the laboratory is addressed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02174467
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  • 2
    Electronic Resource
    Electronic Resource
    MCSS-based predictions of RNA binding sites (1999)
    Springer
    Theoretical chemistry accounts 101 (1999), S. 131-137 
    Details
    ISSN: 1432-2234
    Keywords: Key words: MCSS ; Ligand Design ; RNA ; Binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract. The diversity of RNA tertiary structures provides the basis for specific recognition by proteins or small molecules. To investigate the structural basis and the energetics which control RNA-ligand interactions, favorable RNA binding sites are identified using the MCSS method, which has been employed previously only for protein receptors. Two different RNAs for which the structures have been determined by NMR spectroscopy were examined: two structures of the TAR RNA which contains an arginine binding site, and the structure of the 16S rRNA which contains an aminoglycoside binding site (paromomycin). In accord with the MCSS methodology, the functional groups representing the entire ligand or only part of it (one residue in the case of the aminoglycosides) are first replicated and distributed with random positions and orientations around the target and then energy minimized in the force field of the target RNA. The Coulombic term and the dielectric constant of the force field are adjusted to approximate the effects of solvent-screening and counterions. Optimal force field parameters are determined to reproduce the binding mode of arginine to the TAR RNA. The more favorable binding sites for each residue of the aminoglycoside ligands are then calculated and compared with the binding sites observed experimentally. The predictability of the method is evaluated and refinements are proposed to improve its accuracy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002140050419
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  • 3
    Electronic Resource
    Electronic Resource
    Solution conformations of structured peptides: continuum electrostatics versus distance-dependent dielectric functions (1999)
    Springer
    Theoretical chemistry accounts 101 (1999), S. 194-204 
    Details
    ISSN: 1432-2234
    Keywords: Key words: Helical peptide ; β-Hairpin ; Random coil ; Umbrella sampling ; Multicanonical sampling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract. To compare different implicit solvent potentials, the folding thermodynamics of the helical peptide RN24 and the β-hairpin peptide BH8 are studied by molecular dynamics simulation with adaptive umbrella sampling. As the potential energy functions, the analytical continuum solvent (ACS) potential and three simplified variants, termed EPSR1, EPSR4, and EPSR10, are used. The ACS potential is a combination of the standard CHARMM force field for the internal energy (bonds, angles, dihedrals) and the van der Waals energy with the analytical continuum electrostatic (ACE) potential and a non-polar solvation potential. The EPSR potentials differ from the ACS potential by the use of Coulomb's law with a distance-dependent dielectric function to calculate the electrostatic energy. With the ACS potential, quantitative agreement with experiment is obtained for the helix propensity (RN24: 62% calculated vs 50–60% experiment) and the β-hairpin propensity (BH8: 33% calculated vs 19–37% experiment) of the peptides. During the simulations with the EPSR potentials, no significant formation of secondary structure is observed. It is shown that the preference for coil conformations over conformations with secondary structure by the EPSR potentials is due to an overestimation of the energy of salt bridge formation, independent of the magnitude of the Coulomb energy relative to the other energy terms. Possible improvements of the distance-dependent dielectric functions which may permit their application to the simulation of peptide folding, are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002140050429
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  • 4
    Electronic Resource
    Electronic Resource
    Adaptive umbrella sampling of the potential energy: modified updating procedure of the umbrella potential and application to peptide folding (1999)
    Springer
    Theoretical chemistry accounts 101 (1999), S. 62-66 
    Details
    ISSN: 1432-2234
    Keywords: Key words: Adaptive umbrella sampling ; Multicanonical sampling ; Helical peptide ; β-hairpin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract. Adaptive umbrella sampling of the potential energy is used as a search method to determine the structures and thermodynamics of peptides in solution. It leads to uniform sampling of the potential energy, so as to combine sampling of low-energy conformations that dominate the properties of the system at room temperature with sampling of high-energy conformations that are important for transitions between different minima. A modification of the procedure for updating the umbrella potential is introduced to increase the number of transitions between folded and unfolded conformations. The method does not depend on assumptions about the geometry of the native state. Two peptides with 12 and 13 residues, respectively, are studied using the CHARMM polar-hydrogen energy function and the analytical continuum solvent potential for treatment of solvation. In the original adaptive umbrella sampling simulations of the two peptides, two and six transitions occur between folded and unfolded conformations, respectively, over a simulation time of 10 ns. The modification increases the number of transitions to 6 and 12, respectively, in the same simulation time. The precision of estimates of the average effective energy of the system as a function of temperature and of the contributions to the average effective energy of folded conformations obtained with the adaptive methods is discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002140050407
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  • 5
    Electronic Resource
    Electronic Resource
    A comparative study of ligand-receptor complex binding affinity prediction methods based on glycogen phosphorylase inhibitors (1999)
    Springer
    Journal of computer aided molecular design 13 (1999), S. 243-258 
    Details
    ISSN: 1573-4951
    Keywords: binding affinity prediction ; CoMFA ; genetic neural network ; glycogen phosphorylase inhibitor ; QSAR ; structure-based drug design
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Finding an accurate method for estimating the affinity of protein ligands activity is the most challenging task in computer-aided molecular design. In this study we investigate and compare seven different prediction methods for a set of 30 glycogen phosphorylase (GP) inhibitors with known crystal structures. Five of the methods involve quantitative structure-activity relationships (QSAR) based on the 2D or 3D structures of the GP ligands alone. They are hologram QSAR (HQSAR), receptor surface model (RSM), comparative molecular field analysis (CoMFA), and applications of genetic neural network to similarity matrix (SM/GNN) or conventional descriptors (C2GNN). All five QSAR-based models have good predictivity and yield q2 values ranging from 0.60 to 0.82. The other two methods, LUDI and a structure-based binding energy predictor (SBEP) system, make use of the structures of the ligand-receptor complexes. The weak correlation between biological activities and the LUDI scores of this set of inhibitors suggests that the LUDI scoring function, by itself, may not be a general method for reliable ranking of a congeneric series of compounds. The SBEP system is derived from a set of physical properties that characterizes ligand-receptor interactions. The final neural network model, which yields a q2 value of 0.60, employs four descriptors. A jury method that combines the predictions of the five QSAR-based models leads to an increase in predictivity. A multi-layer scoring system that utilizes all seven prediction methods is proposed for the evaluation of novel GP ligands.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008073215919
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  • 6
    Electronic Resource
    Electronic Resource
    Design of dimerization inhibitors of HIV-1 aspartic proteinase: A computer-based combinatorial approach (2000)
    Springer
    Journal of computer aided molecular design 14 (2000), S. 161-179 
    Details
    ISSN: 1573-4951
    Keywords: de novo design ; finite-difference Poisson–Boltzmann ; HIV-1 aspartic proteinase ; inhibitors of dimerization ; MCSS ; structure-based drug design
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Inhibition of dimerization to the active form of the HIV-1 aspartic proteinase (HIV-1 PR) may be a way to decrease the probability of escape mutations for this viral protein. The Multiple Copy Simultaneous Search (MCSS) methodology was used to generate functionality maps for the dimerization interface of HIV-1 PR. The positions of the MCSS minima of 19 organic fragments, once postprocessed to take into account solvation effects, are in good agreement with experimental data on peptides that bind to the interface. The MCSS minima combined with an approach for computational combinatorial ligand design yielded a set of modified HIV-1 PR C-terminal peptides that are similar to known nanomolar inhibitors of HIV-1 PR dimerization. A number of N-substituted 2,5-diketopiperazines are predicted to be potential dimerization inhibitors of HIV-1 PR.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008146201260
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  • 7
    Electronic Resource
    Electronic Resource
    Functionality map analysis of the active site cleft of human thrombin (1996)
    Springer
    Journal of computer aided molecular design 10 (1996), S. 1-10 
    Details
    ISSN: 1573-4951
    Keywords: Thrombin inhibitors ; Molecular modelling ; Rational drug design ; MCSS method
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary The Multiple Copy Simultaneous Search methodology has been used to construct functionality maps for an extended region of human thrombin, including the active site. This method allows the determination of energetically favorable positions and orientations for functional groups defined by the user on the three-dimensional surface of a protein. The positions of 10 functional group sites are compared with those of corresponding groups of four thrombin-inhibitor complexes. Many, but not all features, of known thrombin inhibitors are reproduced by the method. The results indicate that certain aspects of the binding modes of these inhibitors are not optimal. In addition, suggestions are made for improving binding by interaction with functional group sites on the thrombin surface that are not used by the thrombin inhibitors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00124460
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  • 8
    Electronic Resource
    Electronic Resource
    Protein dynamics: From the native to the unfolded state and back again (1995)
    Springer
    Molecular engineering 5 (1995), S. 55-70 
    Details
    ISSN: 1572-8951
    Keywords: Molecular dynamics ; barnase denaturation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Simulations to study protein unfolding and folding were performed. The unfolding simulations make use of molecular dynamics and treat an atomic model of barnase in aqueous solvent. The cooperative nature of the unfolding transition and the important role of water are described. The folding simulations are based on a bead model of the protein on a cubic lattice. It is shown for the 27-mer model that a large energy gap between the lowest energy (native) state and the excited states is a necessary and sufficient condition for fast folding.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00999578
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