This edition of the Proceedings of the 9th European Symposium on Structure-Activity Relationships: QSAR and Molecular Modelling held from September 7-11, 1992 in Strasbourg, France deals with various areas of structure-activity relationships and their applications in the design of new drugs. The approximately 175 contributions in the book highlight the interdisciplinary approach between QSAR, molecular modelling and databank-based research in the design and development process of new drug candidates, and demonstrates the efficacy of these techniques by introducing rationalization at a very early stage in the discovery of bioactive compounds.
Internationally renowned specialists review methodologies in the field of SAR concepts and computer-assisted drug design, covering such topics as:
- De novo design
- X-ray and NMR-based drug design
- Parameters and interactions.
- Molecular modelling
- Molecular similarity
- 3D QSAR.
Welcome Lecture.- Activity in QSAR: From A major to A minor.- Section I: De novo Design X-ray and NMR-based Drug Design.- Recent advances in de novo molecular design.- New strategies that improve the efficiency of the 3D design of bioactive molecules.- LUDI: A computer program for de novo ligand design.- Docking ligands in the receptor cavity: What have we learned?.- APOLLO pharmacophores and the pseudoreceptor concept.- Molecular modelling contributions to serine protease and serine esterase inhibitor design.- Simple modifications of MD force fields for determination of peptide structures from NMR data.- Section II: Parameters and Interactions.- Multivariate data modeling of new steric, topological and CoMFA- derived substituent parameters.- A structural model for drug interactions with biological membranes: Hydrophobicity, hydrophilicity and amphiphilicity in drug structures.- Relationships between structure and activity based on a partitioning of free energy contributions in the estimation of binding constants.- 2D and 3D lipophilicity parameters in QSAR.- Polar intermolecular interactions encoded in partition coefficients and their interest in QSAR.- Mechanism of retention of benzodiazepines in affinity, reversedphase and adsorption high-performance liquid chromatography in view of quantitative structure-retention relationships.- Analysis of enzyme-ligand interactions in organic solvents: A QSAR approach.- QSAR H-bonding descriptions.- Methods and parameters to describe drug membrane interaction and their use in QSAR.- Conformation calculations of peptides with polar amino acids: Differences by surrounding conditions and by modelling approaches.- The use of neural networks for data analysis in QSAR: Chance effects.- A basic confrontation of Rekker’s revised ?f-system with HPLC retention data obtained on a mixed series of aliphatic and aromatic hydrocarbons.- QSTAR expressions for integral and differential biological response.- Concept and features of EMIL, a system for lead evolution of bioactive compounds.- Interaction terms in Free-Wilson analysis: A QSAR of histamine H2-agonists.- QSAR and environmental toxicology: A challenge for the 1990s.- Section III: Molecular Modelling.- Study of the recognition of the heparin-like pentasaccharides by antithrombin III.- Computer-aided modelling of G-protein coupled receptor: Application to cationic neurotransmitter and mammalian opsin receptors.- Molecular modelling studies on the digitalis binding site of the Na+/K+-ATPase.- Molecular modeling of viral peptides bound to class I MHC proteins.- Theoretical model for the metabolism of caffeine and its inhibition.- The importance of a disulphide bond in the binding of dopamine to the D2 receptor: A molecular modelling study.- Section IV: Molecular Similarity.- Molecular similarity.- Searching for molecular similarity between flexible molecules.- Statistical analysis and shape recognition: Applications to MD simulations, conformational analysis and structure-activity relationships.- Topological approaches to three-dimensional molecular shape.- Section V: 3D QSAR.- Experience with comparative molecular field analysis.- CoMFA as a tool for active site modelling.- Use of the hydrogen-bond potential function in comparative molecular field analysis (CoMFA): An extension of CoMFA.- Experiences with conformationally flexible 3D databases.- GOLPE: An advanced chemometric tool for 3D QSAR problems.- Three dimensional molecular modeling of the ?1a-adrenoceptor: Direct 3D-QSAR modeling of selective antagonists.- New methods for 3D SAR and lead generation in computer-aided drug design.- Posters.- Conformational studies of immunologically active carbocyclic analogues of MDP.- Molecular modelling and high-field NMR techniques for interactions of cognition-activator drugs with cyclodextrins.- Conformational analysis of C3?-substituted pyrimidine nucleosides by X-ray diffraction.- Conformational properties of pyranosyl nucleosides by X-ray diffraction and modelling techniques.- Conformational and lipophilic behaviour of 2-amino-2-oxazolines with antidepressant activity.- Crystal and molecular structures of the calcium carbohydrates: Chloride salt of the lactobionic acid (C12H21O12)?(Ca)2(Cl)? ·4H2O, lactose complex with calcium chloride C12H22O11·CaCl2 ·7H2O and calcium galactonate (C6H11O7)Ca1/2·2 1/2H2O.- Comparison of ligands for the peripheral benzodiazepine receptors using ab initio molecular orbital calculations.- 1-[[4-(Aminoalkoxy)phenyl]sulfonyl] indolizines, a novel class of calcium entry blockers: Relations between chemical structure, steroelectronic properties and anticalcic activity.- Structural and theoretical study of 5-(R)-(methoxymethyl)-3-aryloxazolidin-2-ones, reversible monoamine oxidase inhibitors.- Conformation-activity relationships in the verapamil class of calcium antagonists.- A QSAR evaluation of existing contact allergy database.- Drug-receptor dissociation time: Its dependence on the structure.- Biological systems for measuring mutagenicity and carcinogenicity, and ‘average’ properties of active compounds.- Dipolar, hydrogen bonding and van der Waals forces and their contributions to the partition behaviour of drugs and chemicals.- Molecular modelling of enzymes and receptors involved in carcinogenesis: QSARS and COMPACT-3D.- The study of bioisosterism using molecular transform.- Structure-activity relationships of non-peptide Angiotensin II antagonists.- Prediction of biological activity using continuum regression.- Hyperdimensionality in QSAR: Cutting problems to workable sizes.- CARSO response surface modelling of para-substituted-N-heteroaryl benzylamines antimycotic activities.- Design of more informative molecules for QSAR study in a series of juvenile hormones.- Application of a robust method for detecting outliers in data used for antineoplastic activity prediction.- Application of computed atomic and molecular descriptors in QSAR modelling.- Photoreactivity of coumarin derivatives: Pattern recognition and QSAR studies.- The use of molecular electrostatic potential in QSAR.- Application of QSAR and molecular modelling in designing 1-[4- arylpiperazin-1-yl]-3-thioarylpropanes: A new class of centrally acting hypotensive agents.- Modelling the aquatic toxicity of reactive organic chemicals: Finding descriptors for SN2 reactivity.- Similarity of MEP distributions obtained using several semiempirical and ab initio wave functions: A cluster analysis.- Electrostatic contributions to binding affinity for the enzyme thymidylate 341 synthase and a series of inhibitors.- A simple method to calculate net atomic charges (EMIR): Rapid access to the charge-dependent properties of molecules.- Incorporation of elimination can improve the pseudo-equilibrium description of bioactivity-hydrophobicity-acidity profiles.- Lipophilic and electronic factors influencing the activity of a series of urea ACAT inhibitors: Approaches to model specification.- Prediction of lipophilicity in peptide-like molecules.- Topological lipophilicity potential: A new tool for a fast evaluation of lipophilicity distribution on a molecular graph.- MEPSIM: An integrated computational system for molecular electrostatic potential analysis and comparison.- New van der Waals indicators of shape and size of substituents and molecules for quantitative treatment of steric effects.- Prediction of the log P of typical heteroaromatic compounds by reversed-phase liquid chromatography.- Development of new molecular descriptors using conformational energies from quantum calculations and their application in QSAR-analysis.- Use of molecular modelling in the interpretation of conventional QSAR equations: Inclusion complexes of cyclodextrins with phenobarbital.- Comparison between RPHPLC capacity factors and octanol-water partition coefficients of 9H-xanthene and 9H-thioxanthene derivatives.- The estimation of physicochemical properties by RP18-TLC.- Understanding the enantioselectivity of Mucor miehei lipase.- Calculated log P values: Are they reliable?.- Estimation of aqueous solubility from boiling point.- Calculation of the topological invariants for the excised van der Waals’ surface of a molecule.- Measurement of pKa and log P of water-insoluble substances by potentiometric titration.- Use of surface properties from ab initio calculations to characterize heterocycles.- Length and alignment independent sequence-activity models.- Grid-assisted similarity perception (GRASP): A new method of overlapping molecular structures.- Use of neural networks to predict hydration sites in proteins.- Role of the dipole moment during ligand receptor interaction: A hypothetic static model.- The electroconformational space of the ?-adrenergic receptor: A molecular modelling study of ?-agonists.- Determination of quantitative structure-activity relationships in antiviral metal complexes using molecular mechanics.- A novel automatic docking method for flexible molecules.- Application of neural networks to the 3D-pharmacophore search problem.- Comparative conformational analysis of pyrrolacetic compounds with antiinflammatory activity.- Flexible docking of ligands to receptor sites using genetic algorithms.- Topological pharmacophore evaluation by interactive approach: A case study.- DIGFIT: A superposition generator for flexible molecules.- A combinatorial search of enzyme-ligand docking space using distance geometry, cluster analysis and energy evaluation.- Conformational properties of the transmembrane domains of the human D2-receptor: Comparison with bacteriorhodopsin.- Topography of the huperzine A binding site in AChE: Ab initio docking of reversible inhibitors of AChE into the dynamic enzyme.- Characterization of the pharmacophoric pattern of acetylcholinesterase inhibitors through conformational analysis.- Prolyl-endopeptidase inhibitors: Pharmacophore characterization via conformational analysis and pattern recognition.- Conformational search and transitional states study of arachidonic acid using molecular dynamics and AMI semiempirical calculations.- Conformational analysis of some fentanyl derivatives in relation to the drug-receptor dissociation rate.- Modelling of the 3D structure of Bacillus circulans var. alkalophilus cyclomaltodextrin glucanotransferase and comparison with ?- amylase.- Rational approach towards the synthesis of new ALS-inhibitors.- Molecular dynamics simulations of the complex of adenylate kinase from Escherichia coliEscherichia coli and the inhibitor AP5A.- Uncoupling of CD4 signal transduction with a rationally designed analog.- Modelling of noncompetitive antagonists of the N-Methyl-DAspartate (NMDA) receptor.- Differentiation of ?1and ?2-adrenoceptors agonists using the receptor mapping technique.- Modeling of ?2-adrenoceptors agonists: Specificity of the ?2A-subtype.- Computer modelling and structure-activity relationships of angiotensin II-related compounds.- Molecular modelling studies of PCP binding by arylcyclohexylpiperidines.- Molecular modeling and mutagenic activity of nitro- and aminocarbazoles.- GABAergic activity of triamino-pyridines and triamino-benzenes.- Molecular modelling comparison of potent and selective K-agonists belonging to different chemical structures: A first attempt of ?-receptor mapping.- Design and molecular modelling of antisense pyranosyl oligonucleotides.- Molecular modelling studies with CCK-B receptor antagonists.- A molecular modelling study of dianionic species extraction by dicationic extractants.- A molecular modeling study on the hormone binding site of the estrogen receptor.- Theoretical investigations on the interaction of non-steroidal antiphlogistics with a model of the active site of the human prostaglan-din endoperoxide synthase (‘cyclooxygenase’).- Molecular modelling studies on the enzyme-substrate complex sialidase-N-acetylneuraminic acid and the mechanism of catalysis.- Molecular determinants of the platelet aggregation inhibitory activity of carbamoylpiperidines.- Quantitative description of nucleic acid sequences based on chemical characterization of the monomers.- 3D Modelling of soybean glyoxysomal malate dehydrogenase.- Conformational requirements for interaction of L-glutamate with the metabotropic EAA receptor.- Molecular modelling of G-protein coupled receptors: The interaction between specific ligands and their putative binding sites.- Inductive reasoning in a QSAR intelligent system.- Development of QSARs from incomplete dose-response data using neural networks.- pKa prediction in multiply-substituted phenols: A comparison of multiple linear regression and back-propagation.- An approach to knowledge-based QSAR predictions using the MASCA model.- Skin sensitisation structure-activity relationships for phenols and anilins and application of a qualitative rule-based system:.- Expert system approach for predicting pKa.- Molecular lipophilicity potential as a tool in 3D QSAR: Method development and applications.- An active site model of phenylethanolamine N-methyltransferase using CoMFA.- Use of the GRID program in the 3D QSAR of a series of calcium channel agonists.- MLR and PLS: A comparison of the techniques applied to the QSAR analysis of a series of structurally diverse biologically active compounds.- Comparative molecular field analysis of CCK-A antagonists using field fit as alignment technique.- 3D QSAR of insecticidal dioxatricycloalkene and its related compounds.- Use of advanced chemometric tools and comparison of different 3D descriptors in QSAR analysis of prazosin analog ?1-adrenergic antagonists.- Pharmacophore development of (-)-cocaine analogs for the dopamine, serotonin, and norepinephrine uptake sites using a QSAR and CoMFA approach.- Partitioning behaviour of piracetam-type cogniton enhancers.- Partition behavior of solvents, drugs and chemicals.- Use of molecular electrostatic potentials for analysis of anticonvulsant activities of phenylsuccinimides.- Application of molecular orbital calculations to the QSAR analysis of enzyme-ligand interactions.- QSARs of fathead minnow and Microtox toxicity data using canonical correlation analysis.- The Hypersurface Iterative Projection (HIP) method and its application to bicyclic pyrazolidinone antibacterial agents.- QSAR analysis of time- and dose-dependent in vivo drug effects using artificial neural networks.- Brain penetration and H-bonding capacity.- Antiserotoninergic activity of 2-aminoethylbenzocyclanones in rat aorta: Structure-activity relationships.- Estrogenic activity: An example of considering effectuation models in biological data interpretation and QSAR.- QSAR and quantum-mechanical studies in cytotoxic series of nitroand aminocarbazoles.- QSAR analysis of the toxicological activity of N, N-(dimethylamino)ethyl-benzoate hydrochlorides.- QSAR in the nonsteroidal anti-inflammatory agents: The fenamic acids.- Application of QSAR of substituted benzamides for prediction of their biodistribution as tracer radioligands in the brain.- QSAR by MTD for inhibition of keratinization of tracheal cells in organ culture by retinoids.- QSAR of some antibacterial active isosteric heterocyclic compounds against an enterobacter.- The effect of ortho substitution of the 2,4-diamino-5-(x-benzyl) pyrimidine nucleus on the inhibition of avian and bacterial dihydrofolate reductase.- A note on excess toxicity of acetylenic alcohols to ciliate Tetrahymena pyriformis.- Different structural requirements for the inhibitory activity of furan carboxanilide derivatives against SDC for either wild or mutant strains of Ustilago maydis.- The value of the local lymph node assay in the development of QSARs for skin sensitization potential.- Author index.
