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Poster Session I. New Developments and Applications of Multivariate QSAR

Poster Session I. New Developments and Applications of Multivariate QSAR

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CONTENTS



Section I: Overview

Strategies for Molecular Design Beyond the Millennium ...................................................

James P. Snyder and Forrest D. Snyder



..3



Section 11: New Developments and Applications of Multivariate QSAR

Multivariate Design and Modelling in QSAR, Combinatorial Chemistry, and

Bioinformatics ..........................................................................................................

.27

Svante Wold, Michael Sjostrom, Per M. Andersson, Anna Linusson, Maria Edman,

Torbjorn Lundstedt, Bo NordCn, Maria Sandberg, and Lise-Lott Uppgird

QSAR Study of PAH Carcinogenic Activities: Test of a General Model for Molecular

Similarity Analysis ....................................................................................................

William C. Herndon, Hung-Ta Chen, Yumei Zhang, and Gabrielle Rum



47



Comparative Molecular Field Analysis of Aminopyridazine Acetylcholinesterase

Inhibitors ....................................................................................................................

Wolfgang Sippl, Jean-Marie Contreras, Yveline Rival, and Camille G. Wermuth



53



The Influence of Structure Representation on QSAR Modelling ..........................................

Marjana NoviE, Matevi Pompe, and Jure Zupan



59



The Constrained Principal Property (CPP) Space in QSAR-Directional and

Non-Directional Modelling Approaches....................................................................

Lennart Eriksson, Patrik Andersson, Erik Johansson, Mats Tysklind,

Maria Sandberg, and Svante Wold



65



Section 111: The Future of 3D-QSAR

Handling Information from 3D Grid Maps for QSAR Studies..............................................

Gabriele Cruciani, Manuel Pastor, and Sergio Clementi

Gaussian-Based Approaches to Protein-Structure Similarity ................................................

Jordi Mestres, Douglas C. Rohrer, and Gerald M. Maggiora



73

83



Molecular Field-Derived Descriptors for the Multivariate Modeling of Pharmacokinetic

Data ........................................................................................................................... .89

Wolfgang Guba and Gabriele Cruciani



vii



Validating Novel QSAR Descriptors for Use in Diversity Analysis .....................................

Robert D. Clark, Michael Brusati, Robert Jilek, Trevor Heritage,

and Richard D. Cramer



95



Section IV: Prediction of Ligand-Protein Binding

Structural and Energetic Aspects of Protein-Ligand Binding in Drug Design ......................



103



Gerhard Klebe, Markus Bohm, Frank Dullweber, Ulrich Gradler, Holger Gohlke,

and Manfred Hendlich

Use of MD-Derived Shape Descriptors as a Novel Way to Predict the in Vivo Activity of

Flexible Molecules: The Case of New Immunosuppressive Peptides ....................... 111

Abdelaziz Yasri, Michel Kaczorek, Roger Lahana, Gerard Grassy, and

Roland Buelow

A View on Affinity and Selectivity of Nonpeptidic Matrix Metalloproteinase Inhibitors

from the Perspective of Ligands and Target ..............................................................

Hans Matter and Wilfried Schwab



123



On the Use of SCRF Methods in Drug Design Studies .........................................................

Modesto Orozco, Carles Colominas, Xavier Barril, and F. Javier Luque



129



3D-QSAR Study of 1,4-Dihydropyridines Reveals Distinct Molecular Requirements of

Their Binding Site in the Resting and the Inactivated State of Voltage-Gated

Calcium Channels ......................................................................................................

Klaus-Jurgen Schleifer, Edith Tot, and Hans-Dieter Holtje

Pharmacophore Development for the interaction of Cytochrome P450 1A2 with Its

Substrates and Inhibitors ............................................................................................

Elena L6pez-de-Brifias, Juan J. Lozano, Nuria B. Centeno, Jordi Segura,

Marisa Gonzilez, Rafael de la Torre, and Ferran Sanz



135



141



Section V: Computational Aspects of Molecular Diversity and Combinatorial

Libraries

Analysis of Large, High-Throughput Screening Data Using Recursive Partitioning ............149

S. Stanley Young and Jerome Sacks

3D Structure Descriptors for Biological .Activity ..................................................................

Johann Gasteiger, Sandra Handschuh, Markus C. Hemmer, Thomas Kleinoder,

Christof H. Schwab, Andreas Teckentrup, Jens Sadowski, and Markus Wagener



157



Fragment-Based Screening of Ligand Databases ..................................................................

Christian Lemmen and Thomas Lengauer



169



The Computer Simulation of High Throughput Screening of Bioactive Molecules .............175

Frank R. Burden and David A. Winkler



Section VI: Affinity and Efficacy Models of G-Protein Coupled Receptors

5-HTIAReceptors Mapping by Conformational Analysis (2D NOESY/MM) and

“THREE WAY MODELLING’ (HASL, CoMFA, PARM) ....................................

Maria Santagati, Arthur Doweyko, Andrea Santagati, Maria Modica,

Salvatore Guccione, Chen Hongming, Gloria Uccello Barretta,

and Federica Balzano



viii



183



Design and Activity Estimation of a New Class of Analgesics .............................................

Slavomir Filipek and Danuta Pawlak



195



Unified Pharmacophoric Model for Cannabinoids and Aminoalkylindoles.......................... 201

Joong-Youn Shim, Elizabeth R. Collantes, William J. Welsh, and Allyn C. Howlett

Chemometric Detection of Binding Sites of 7TM Receptors ................................................

Monica Clementi, Sara Clementi, Sergio Clementi, Gabriele Cruciani,

Manuel Pastor. and Jonas E. Nilsson



207



Section VII: New Methods in Drug Discovery

SpecMat: Spectra as Molecular Descriptors for the Prediction of Biological Activity .........215

R. Bursi and V.J. van Geerestein



Hydrogen Bond Contributions to Properties and Activities of Chemicals and Drugs ..........221

Oleg A. Raevsky, Klaus J. Schaper, Han van de Waterbeemd,

and James W. McFarland



Section VIII: Modeling of Membrane Penetration

Predicting Peptide Absorption ...............................................................................................

Lene H. Krarup, Anders Berglund, Maria Sandberg, Inge Thoger Christensen,

Lars Hovgaard, and Sven Frokjaer

Physicochemical High Throughput Screening (pC-HTS): Determination of Membrane

Permeability, Partitioning and Solubility .................................................................

Manfred Kansy, Krystyna Kratzat, Isabelle Parrilla, Frank Senner,

and Bjorn Wagner

Understanding and Estimating Membranemater Partition Coefficients: Approaches to

Derive Quantitative Structure Property Relationships ...............................................

Wouter H. J. Vaes, EAaut Urrestarazu Ramos, Henk J. M. Verhaar,

Christopher J. Cramer, and Joop L. M. Hermens



23 1



.237



245



Prediction of Human Intestinal Absorption of Drug Compounds from Molecular

Structure .................................................................................................................... .249

M. D. Wessel, P. C. Jurs, J. W. Tolan, and S. M. Muskal



Section IX: Poster Presentations

Poster Session I: New Developments and Applications of Multivariate QSAR

Free-Wilson-Type QSAR Analyses Using Linear and Nonlinear Regression Techniques ...261

Klaus-Jiirgen Schaper

QSAR Studies of Picrodendrins and Related Terpenoids-Structural Differences

between Antagonist Binding Sites on GABA Receptors of Insects and Mammals ..263

Miki Akamatsu, Yoshihisa Ozoe, Taizo Higata, Izumi Ikeda, Kazuo Mochida,

Kazuo Koike, Taichi Ohmoto, Tamotsu Nikaido, and Tamio Ueno

Molecular Lipophilicity Descriptors: A Multivariate Analysis ............................................. 265

Raimund Mannhold and Gabriele Cruciani



ix



World Wide Web-Based Calculation of Substituent Parameters for QSAR Studies ............267

Peter Ertl

COMBINE and Free-Wilson QSAR Analysis of Nuclear Receptor-DNA Binding .............269

Sanja Tomic, Lennart Nilsson, and Rebecca C. Wade

QSAR Model Validation ......................................................................................................

Erik Johansson, Lennart Eriksson, Maria Sandberg, and Svante Wold



.271



QSPR Prediction of Henry’s Law Constant: Improved Correlation with New Parameters ..273

John C. Dearden, Shazia A. Ahmed, Mark T. D. Cronin, and Janeth A. Sharra

QSAR of a Series of Carnitine Acetyl Transferase (CAT) Substrates ..................................

G. Gallo, M. Mabilia, M. Santaniello, M. 0. Tinti, and P. Chiodi



275



“Classical” and Quantum Mechanical Descriptors for Phenolic Inhibition of Bacterial

Growth .....................................................................................................................

S. Shapiro and D. Turner



..277



Hydrogen Bond Acceptor and Donor Factors, C, and C,: New QSAR Descriptors ..............280

James W. McFarland, Oleg A. Raevsky, and Wendell W. Wilkerson

Development and Validation of a Novel Variable Selection Technique with Application

282

to QSAR Studies ........................................................................................................

Chris L. Waller and Mary P. Bradley

QSAR Studies of Environmental Estrogens ..........................................................................

M. G. B. Drew, N. R. Price, andH. J. Wood



284



Quantitative Structure-Activity Relationship of Antimutagenic Benzalacetones and

Related Compounds ..................................................................................................

Chisako Yamagami, Noriko Motohashi, and Miki Akamatsu



.286



Multivariate Regression Excels Neural Networks, Genetic Algorithm and Partial

Least-Squares in QSAR Modeling ............................................................................ 288

Bono LuEic and Nenad Trinajstic

Structure-Activity Relationships of Nitrofuran Derivatives with Antibacterial Activity ......290

JosC Ricardo Pires, AstrCa Giesbrecht, Suely L.Gomes, and Antonia T. do-Amaral

QSAR Approach for the Selection of Congeneric Compounds with Similar Toxicological

Modes of Action ....................................................................................................... 292

Paola Gramatica, Federica Consolaro, Marco Vighi, Roberto Todeschini,

Antonio Finizio, and Michael Faust

Strategies for Selection of Test Compounds in Structure-Affinity Modelling of Active

Carbon Adsorption Performance: A Multivariate Approach .....................................

L.-G. Hammarstrom, I. Fangmark, P. G. Jonsson, P. R. Norman, A. L. Ness,

S. L. McFarlane, and N. M. Osmond



293



Design and QSAR of Dihydropyrazol0[4,3-~]Quinolinonesas PDE4 Inhibitors .................295

M. Lbpez, V. Segarra, M. I. Crespo, J. Gracia, T. DomCnech, J. Beleta, H. Ryder,

and J. M. Palacios

QSAR Based on Biological Microcalorimetry: On the Study of the Interaction between

Hydrazides and Escherichia coli and Saccharomyces cerevisiae ............................. .297

Maria Luiza Cruzera Montanari, Anthony Beezer, and Carlos Albert0 Montanari

Cinnoline Analogs of Quinolones: Structural Consequences of the N Atom Introduction

.299

in the Position 2 ........................................................................................................

Marek L. Glbwka, Dariusz Martynowski, Andrzej Olczak, and Alina Staszewska



X



Joint Continuum Regression for Analysis of Multiple Responses ........................................

Martyn G. Ford, David W. Salt, and Jon Malpass



301



Putative Pharmacophores for Flexible Pyrethroid Insecticides .............................................

Martyn G. Ford, Neil E. Hoare, Brian D. Hudson, Thomas G. Nevell,

and John A. Wyatt



303



Predicting Maximum Bioactivity of Dihydrofolate Reductase Inhibitors...........................

Matevi Pompe, Marjana NoviE, Jure Zupan, and Marjan Veber



..305



Evaluation of Carcinogenicity of the Elements by Using Nonlinear Mapping .....................

Alexander A. Ivanov



307



Poster Session 11: The Future of 3D-QSAR

Partition Coefficients of Binary Mixtures of Chemicals: Possibility for the QSAR

Analysis ..................................................................................................................... 3 11

Milofi Tichy, Marian Rucki, Vaclav B. Dohalsky, and Ladislav Felt1

A CoMFA Study on Antileishmaniasis Bisamidines ............................................................

Carlos Albert0 Montanari



3 14



Antileishmanial Chalcones: Statistical Design and 3D-QSAR Analysis ..............................

Simon F. Nielsen, S. Brogger Christensen, A. Kharazmi, and T. Liljefors



3 16



Chemical Function Based Alignment Generation for 3D QSAR of Highly Flexible

Platelet Aggregation Inhibitors ..................................................................................

Rtmy D. Hoffmann, Thieny Langer, Peter Lukavsky, and Michael Winger



3 18



3D QSAR on Mutagenic Heterocyclic Amines That are Substrates of

Cytochrome P450 1A2...............................................................................................

Juan J. Lozano, Manuel Pastor, Federico Gago, Gabriele Cruciani,

Nuria B. Centeno, and Ferran Sanz



321



Application of 4D-QSAR Analysis to a Set of Prostaglandin, PGF,a, Analogs ...................323

C. Duraiswami, P. J. Madhav, and A. J. Hopfinger

Determination of the Cholecalciferol-LipidComplex Using a Combination of

Comparative Modelling and N M R Spectroscopy......................................................

Mariagrazia Sarpietro, Mario Marino, Antonio Cambria, Gloria Uccello Barretta,

Federica Balzano, and Salvatore Guccione

Comparative Binding Energy (COMBINE) Analysis on a Series of Glycogen

Phosphorylase Inhibitors: Comparison with GRID/GOLPE Models ........................

Manuel Pastor, Federico Gago, and Gabriele Cruciani

EVA QSAR: Development of Models with Enhanced Predictivity (EVA-GA)

David B. Turner and Peter Willett



325



329



..................33 1



3D-QSAR, GRID Descriptors and Chemometric Tools in the Development of Selective

Antagonists of Muscarinic Receptor.......................................................................... 334

Paola Gratteri, Gabriele Cruciani, Serena Scapecchi, M. Novella Romanelli, and

Fabrizio Melani

Small Cyclic Peptide SAR Study Using APEX-3D System: Somatostatin Receptor Type

2 (SSTRZ) Specific Pharmacophores ......................................................................... 336

Larisa Golender, Rakefet Rosenfeld, and Erich R. Vorpagel



xi



3D Quantitative Structure-Activity Relationship (CoMFA) Study of Heterocyclic

Arylpiperazine Derivatives with 5-HTIA,Activity......................................................

Ildikd Magd6, Istvin Laszlovszky, Tibor Acs, and Gyorgy Domfiny



338



Molecular Similarity Analysis and 3D-QSAR of Neonicotinoid Insecticides .......................

Masayuki Sukekawa and Akira Nakayama



340



3D-SAR Studies on a Series of Sulfonate Dyes as Protection Agents against p-amyloid

Induced in Vitro Neurotoxicity ..................................................................................

M. G. Cima, G. Gallo, M. Mabilia, M. 0.Tinti, M. Castorina, C. Pisano,

and E. Tassoni



342



A New Molecular Structure Representation: Spectral Weighted Molecular (SWM)

Signals and Spectral Weighted Invariant Molecular (SWIM) Descriptors ................344

Roberto Todeschini, Viviana Consonni, David Galvagni, and Paola Gramatica

3D QSAR of Prolyl 4-Hydroxylase Inhibitors ......................................................................

K.-H. Baringhaus, V. Guenzler-Pukall, G. Schubert, and K. Weidmann



345



Aromatase Inhibitors: Comparison between a CoMFA Model and the Enzyme Active

Site .............................................................................................................................

Andrea Cavalli, Maurizio Recanatini, Giovanni Greco, and Ettore Novellino



347



Imidazoline Receptor Ligands-Molecular Modeling and 3D-QSAR CoMFA ...................349

C. Marot, N. Baurin, J. Y . MCrour, G. Guillaumet, P. Renard, and L. Morin-Allory



Poster Session 111: Prediction of Eigand-Protein Binding

Reversible Inhibition of MAO-A and B by Diazoheterocyclic Compounds: Development

of QSAWCoMFA Models ......................................................................................... 353

Cosimo D. Altomare, Antonio Carrieri, Saverio Cellamare, Luciana S u m o ,

Angelo Carotti, Pierre-Alain Canupt, and Bernard Testa

Modelling of the 5-HT2AReceptor and Its Ligand Complexes ..............................................

Estrella Lozoya, Maria Isabel Loza, and Ferran Sanz



355



Towards the Understanding of Species Selectivity and Resistance of Antimalarial DHFR

357

Inhibitors ....................................................................................................................

Thomas Lemcke, Jnge Thoger Christensen, and Flemming Steen Jorgensen

Modeling of Suramin-TNFa Interactions ............................................................................. .359

Carola Marani Toro, Massimo Mabilia, Francesca Mancini, Marilena Giannangeli,

and Claudio Milanese

De Novo Design of Inhibitors of Protein Tyrosine Kinase pp60'""

T. Langer, M. A. Konig, G. Schischkow, and S. Guccione



.......................................



361



Elucidation of Active Conformations of Drugs Using Conformer Sampling by Molecular

Dynamics Calculations and Molecular Overlay ........................................................ 363

Shuichi Hirono and Kazuhiko Iwase

Differences in Agonist Binding Pattern for the GABA, and the AMPA Receptors

Illustrated by High-Level ab Znitio Calculations .......................................................

Lena Tagmose, Lene Merete Hansen, Per-Ola Norrby, and Tommy Liljefors



365



Stabilization of the Ammonium-Carboxylate Ion-Pair by an Aromatic Ring .......................

Tommy Liljefors and Per-Ola Norrby



367



xii



Structural Requirements for Binding to Cannabinoid Receptors ..........................................

Maria Fichera, Alfred0 Bianchi, Gabriele Cruciani, and Giuseppe Musumarra



369



Design, Synthesis, and Testing of Novel Inhibitors of Cell Adhesion ..................................

David T. Manallack, John G. Montana, Paul V. Murphy, Rod E. Hubbard, and



371



Richard J. K. Taylor

Conformational Analysis and Pharmacophore Identification of Potential Drugs for

Osteoporosis ...............................................................................................................

Jan Hgst, Inge Thgger Christensen, and Hemming Steen Jargensen



373



Molecular Modelling Study of DNA Adducts of BhR3464: A New Phase I Clinical

Agent. .........................................................................................................................

G. De Cillis, E. Fioravanzo, M. Mabilia, J. Cox, and N. Fmeil



375



Prediction of Activity for a Set of Flavonoids against HIV- 1 Integrase ................................

J m o Huuskonen, Heikki Vuorela, and Raimo Hiltunen



377



Structure-Based Discovery of Inhibitors of an Essential Purine Salvage Enzyme in

Tritrichomonasfoetus ................................................................................................

Ronald M. A. Knegtel, John R. Somoza, A. Geoffrey Skillman Jr.,

Narsimha Mungala, Connie M. Oshiro, Solomon Mpoke, Shinichi Katakura,

Robert J. Fletterick, Irwin D. Kuntz, and Ching C. Wang

A 3D-Pharmacophore Model for Dopamine D4Receptor Antagonists .................................

Jonas Bostrom, Klaus Gundertofte, and Tommy Liljefors



.380



382



Molecular Modeling and Structure-Based Design of Direct Calcineurin Inhibitors .............384

Xinjun J. Hou, John H. Tatlock, M. Angelica Linton, Charles R. Kissinger,

Laura A. Pelletier, Richard E. Showalter, Anna Tempczyk, and J. Ernest Villafranca

Conformational Flexibility and Receptor Interaction ............................................................

Lambert H. M. Janssen



386



Investigating the Mimetic Potential of P-Turn Mimetics ......................................................

Susanne Winiwarter, Anders Hallberg, and Anders KarlBn



388



Conformational Aspects of the Interaction of New 2,4-Dihydroxyacetophenone

Derivatives with Leukotriene Receptors ....................................................................

Miroslav Kuchaf, Antonin Jandera, Vojt6ch KmoniCek, Bohumila 8rfmov6, and

Bohdan Schneider

Conformational Studies of Poly(Methy1idene Malonate 2.1.2) .............................................

Eric Vangrevelinghe, Pascal Breton, Nicole Bru, and Luc Morin-Allory

A Peptidic Binding Site Model for PDE 4 Inhibitors ............................................................

E. E. Polymeropoulos and N. Hofgen



390



393

395



Molecular Dynamics Simulations of the Binding of GnRH to a Model GnRH Receptor .....397

A.M. ter Laak, R. Kuhne, G. Krause, E. E. Polymeropoulos, B. Kutscher,

and E. Gunther

Analysis of Affinities of Penicillins for a Class C P-Lactamase by Molecular Dynamics

Simulations ...............................................................................................................

.399

Keiichi Tsuchida, Noriyuki Yamaotsu, and Shuichi Hirono

Theoretical Approaches for Rational Design of Proteins ......................................................

JiE Damborskg



401



xiii



Amisulpride, Sultopride, and Sulpiride: Comparison of Conformational and

Physico-Chemical Properties

.............................................................................

, Philippe Poirier, Anne Olivier,

Audrey Blomme, Laurence Con

Jean-Jacques Koenig, Mireille Sevrin, Francois Durant, and Pascal George

Entropic Trapping: Its Possible Role in Biochemical Systems .............................................

Adolf Miklavc and Darko Kocjan



404



406



Structural Requirements to Obtain Potent CAXX Mimic p2 1-Ras-Farnesyltransferase



Inhibitors....................................................................................................................



408



A. Laoui

Hydrogen-Bonding Hotspots as an Aid for Site-Directed Drug Design ...............................

James E. J. Mills and Philip M. Dean



410



Superposition of Flexible Ligands to Predict Positions of Receptor Hydrogen-Bonding

Atoms ........................................................................................................................ 412

James E. J. Mills and Philip M. Dean

Comparative Molecular Field Analysis of Multidrug Resistance Modifiers ........................

Ilza K. Pajeva and Michael Wiese



4 14



Pharmacophore Model of Endothelin Antagonists .......

Mitsuo Takahashi, Kuniya Sakurai, Seji Niwa. an



,416



The Electron-Topological Method

M): Its Further Development and Use in the

Problems of' SAR Study .....

.................................................................................

Nathaly M. Shvets and Anatholy S. Dimoglo



418



Poster Session IV: Computational Aspects of Molecular Diversity and

Combinatorial Libraries

MOLDIVS-A New Program for Molecular Similarity and Diversity Calculations...........423

Vadim A. Gerasimenko, Sergei V. Trepalin, and Oleg A. Raevsky

Easy Does It: Reducing Complexity 'in Ligand-Protein Docking .........................................

Djamal Bouzida, Daniel K. Gehlhaar. and Paul A. Rejto



425



Study of the Molecular Similarity among Three HIV Reverse Transcriptase Inhibitors in

Order to Validate GAGS. a Genetic Algorithm for Graph Similarity Search ...........427

Nathalie Meurice, Gerald M. Maggiora, and Daniel P. Vercauteren

A Decision Tree Learning Approach for the Classification and Analysis of HighThroughput Screening Data ....................................................................................... 429

Michael F. M. Engels, Hans De Winter. and Jan P. Tollenaere



Poster Session V: Affinity and Efficacy Models of G-Protein Coupled Receptors

Application of PARM to Constructing and Comparing 5-HT,, and a , Receptor Models ....433

Maria Santagati, Hongming Chen, Andrea Santagati, Maria Modica,

Salvatore Guccione, Gloria Uccello Barretta, and Federica Balzano

A Novel Computational Method for Predicting the Transmembranal Structure of GProtein Coupled Anaphylatoxin Receptors, C5AR and C3AR .................................

Naomi Siew, Anwar Rayan,Wilfried Bautsch, and Amiram Goldblum



440



Receptor-Based Molecular Diversity: Analysis of HIV Protease Inhibitors ........................

Tim D. J. Perkins, Nasfim Haque, and Philip M. Dean



442



xiv



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