Computer-Assisted Lead Finding and Optimization: Current Tools for Medicinal Chemistry

Description

Computer-assisted techniques are well-integrated in modern drug discovery and used for the finding of new leads, the optimization of receptor or enzyme affinity, as well as of pharmacokinetic and physicochemical properties. In this book an account is found of current strategies used in computer-assisted drug design. Important topics include progress in chemometrics, molecular modeling and three-dimensional QSAR approaches. Relatively new mathematical methods such as genetic algorithms or artificial neural networks and fuzzy logic have found their application in rational molecular design. As is amply illustrated, based on recent developments in these disciplines, important progress has been made in lead finding strategies. This is of great importance to the pharmaceutical industry. Thus, all scientists investigating quantitative structure-activity relationships in their broadest sense, in medicinal, agricultural, or environmental chemistry will benefit from this book.Content: Chapter 1 A General View on Similarity and QSAR Studies (pages 7–28): Hugo KubinyiChapter 2 Prediction of Acute Mammalian Toxicity from Molecular Structure for a Diverse Set of Substituted Anilines Using Regression Analysis and Computational Neural Networks (pages 29–48): Stephen Roger Johnson and Peter C. JursChapter 3 Modeling without Boundary Conditions: An Issue in QSAR Validation (pages 49–63): Alessandro Giuliani and Romualdo BenigniChapter 4 INLR (Implicit Non?linear Latent variable Regression). II. Blockscaling of Expanded Terms with QSAR Examples (pages 65–79): Anders Berglund and Svante WoldChapter 5 MOLSURF ? a Generator of Chemical Descriptors for QSAR (pages 81–92): Per SjobergChapter 6 Kohonen Neural Network: A Novel Approach to Search for Bioisosteric Groups (pages 93–106): Soheila Anzali, Gerhard Barnickel, Michael Krug, Markus Wagener and Johann GasteigerChapter 7 Genetic Selection of Test Series (pages 107–122): James Devillers and Daniel DomineChapter 8 Combinatorial Docking (pages 123–133): Hans?Joachim BohmChapter 9 Quantification of Molecular Similarity and Its Application to Combinatorial Chemistry (pages 135–156): Richard A. Lewis, Andrew C. Good and Stephen D. PickettChapter 10 Exploiting Molecular Diversity: Pharmacophore Searching and Compound Clustering (pages 157–178): Vincent J. van Geerestein, Hans Hamersma and Steven P. van HeldenChapter 11 On the Benefits of Attractive Pseudo?Potentials in a Genetic Algorithm Approach for Structure?Based Library Screening (pages 179–188): Jochen Antel, Ingmar Reuter and Dietmar SchomburgChapter 12 Intelligent Combinatorial Libraries (pages 189–208): Torbjorn Lundstedt, Sergio Clementi, Gabriele Cruciani, Manual Pastor, Nouna Kettaneh, Per M. Andersson, Anna Linusson, Michael Sjostrom, Svante Wold and Bo NordenChapter 13 Molecular Dynamics Simulations As a Tool to Investigate the Three?Dimensional Diversity of Peptide and Pseudopeptide Libraries (pages 209–221): Gerard Grassy, Abdelaziz Yasri, Pierre Sans, Anne?Marie Armbruster, Roger Lahana and Jean?Luc FauchereChapter 14 CATALYST Pharmacophore Models and Their Utility As Queries for Searching 3D Databases (pages 223–240): Peter W. Sprague and Remy HoffmannChapter 15 The Nature and Geometry of Intermolecular Interactions: Combination of 3D?Database Information with Theoretical Tools (pages 241–252): Jos P. M. Lommerse, Robin Taylor, Frank H. Allen and Sarah L. PriceChapter 16 Non?supervised Neural Networks: A New Classification Tool to Process Large Databases (pages 253–264): Dmitri B. Kireev, Frederic Ros, Philippe Bernard, Jacques R. Chretien and Natalia RozhkovaChapter 17 Physicochemical Properties in Drug Metabolism and Pharmacokinetics (pages 265–276): Dennis A SmithChapter 18 Experimental and Theoretical Predictions of Intestinal Drug Absorption (pages 277–289): Katrin Palm, Per Artursson and Kristina LuthmanChapter 19 QSAR Approaches in Mutagenicity and Carcinogenicity Estimation (pages 291–312): Romualdo Benigni and Alessandro GiulianiChapter 20 Dealing with Metabolic Variability during Drug Development (pages 313–331): Luc P. Balant, Marianne Gex?Fabry and Effie A. Balant?GorgiaChapter 21 Molecular Modelling of Cytochromes P450 (pages 333–354): David F. V. LewisChapter 22 Relative Stabilities of Nitrenium Intermediates in Carbazoles Mutagenic Series (pages 355–366): Stephane Chemtob, Christiane Mercier, Veronique Andre and Pascal GauduchonChapter 23 Hydrogen Bond Strength Estimation by Means of the HYBOT Program Package (pages 367–378): Oleg A. RaevskyChapter 24 Region Selection in 3D?QSAR (pages 379–395): Gabriele Cruciani, Manuel Pastor and Sergio ClementiChapter 25 The FLEX Approach: An Alternative for Receptor?Ligand Docking and Computing Crystal Conformations (pages 397–420): Thomas LengauerChapter 26 Molecular Partial Similarity Using Surface?Volume Comparisons (pages 421–432): Tim D. J. Perkins and Philip M. DeanChapter 27 Multiple Field Alignment of Flexible Molecules (pages 433–442): Michael Lipkin, David Salt, Watcyn Wynn and Martyn FordChapter 28 A Stereoselective Pharmacophoric Model of the Serotonin Re?uptake Site (pages 443–459): Klaus Gundertofte, Klaus P. Bogeso and Tommy LiljeforsChapter 29 3D?QSAR Analysis of the Binding of Triazine Herbicides to a Monoclonal Antibody (pages 461–471): Roger Lahana, Peter McWilliams, John Holland and W. Graham RichardsChapter 30 The Role of Water in Receptor?Ligand Interactions. A 3D?QSAR Approach (pages 473–484): Manuel Pastor and Gabriele CrucianiChapter 31 Modelling of the Interactions of Some Inhibitors with the PGHS?1 by BIODOCK ? a Stochastic Approach to the Automated Docking of Ligands to Biomacromolecules (pages 485–495): Alessandro Pedretti, Anna Maria Villa, Luigi Villa and Giulio VistoliChapter 32 Development of a Genetic Algorithm Method Especially Designed for the Comparison of Molecular Models: Application to the Elucidation of the Benzodiazepine Receptor Pharmacophore (pages 497–509): Nathalie Meurice, Laurence Leherte, Daniel P. Vercauteren, Jean?Jacques Bourguignon and Camille G. WermuthChapter 33 Signal Transduction via G Protein?Coupled Receptors: Ternary Complexes As Secondary Proton Pumps and GTP Synthases (pages 511–526): Paul H. J. Nederkoorn and Henk TimmermanChapter 34 Complex Systems: On the Simulation of Nature and the Nature of Simulation: The Chaotic Hierarchy and Interactive New Media Installations (pages 527–542): Michael Klein