Quantitative Molecular Pharmacology and Informatics in Drug Discovery

by Lutz, Michael; Kenakin, Terry

• ISBN13: 9780471988618
• ISBN10: 0471988618
• Edition: 1st
• Format: Hardcover
• Copyright: 2000-01-10
• Publisher: WILEY

Summary

Quantitative Molecular Pharmacology and Informatics in Drug Discovery Michael Lutz, Section Head, Cheminformatics Group and Terry Kenakin, Principal Research Scientist, Glaxo Wellcome Research and Development, Research Triangle Park, NC, USA Quantitative Molecular Pharmacology and Informatics in Drug Discovery combines pharmacology, genetics and statistics to provide a complete guide to the modern drug discovery process. The book discusses the pharmacology of drug testing and provides a detailed description of the statistical methods used to analyze the resulting data. Application of genetic and genomic tools for identification of biological targets is reviewed in the context of drug discovery projects. Covering both the theoretical principles upon which the techniques are based and the practicalities of drug discovery, this informative guide. * outlines in step-by-step detail the advantages and disadvantages of each technology and approach and links these to the type of chemical target being sought after in the drug discovery process; and, * provides excellent demonstrations of how to use powerful pharmacological and statistical tools to optimize high-throughput screening assays. Written by two internationally known and well-regarded experts, this book is an essential reference for research and development scientists working in the pharmaceutical and biotechnology industries. It will also be useful for postgraduates studying pharmacology and applied statistics.

Author Biography

Michael Lutz is the author of Quantitative Molecular Pharmacology and Informatics in Drug Discovery, published by Wiley.

Terry Kenakin is the author of Quantitative Molecular Pharmacology and Informatics in Drug Discovery, published by Wiley.

Table of Contents

Preface	xiii
Acknowledgements	xvii
Drug Discovery	1	(32)
Introduction	1	(1)
The organizational structure of this book	1	(1)
The drug discovery process	2	(18)
Clinical genetics and target selection	3	(6)
Assay and screen development	9	(5)
Compound selection and library design	14	(4)
Optimization of lead compounds for use in humans	18	(2)
Pharmacological definitions	20	(4)
Drug receptor theory	24	(1)
Specificity and selectivity	25	(2)
Null procedures	27	(1)
Conclusions	27	(2)
References	29	(1)
Further reading	30	(3)
Measurement of Drug Affinity	33	(30)
Introduction	33	(1)
The chemical nature of affinity	33	(1)
The Langmuir adsorption isotherm: direct measurement of affinity	33	(4)
Indirect measurement of affinity	37	(20)
Drug antagonism	37	(3)
Competitive antagonism	40	(2)
Competitive antagonism in experiments of pharmacological function: Schild analysis	42	(3)
Affinity of competitive antagonists in binding studies	45	(2)
Competitive antagonism with ligands that produce response: partial agonists	47	(1)
Allosteric antagonism: studies of receptor function	48	(6)
Irreversible antagonism	54	(3)
System vs. receptor-based estimates of affinity	57	(3)
The effect of two-stage binding on observed affinity	57	(1)
The redistribution of receptor binding species	58	(2)
Conclusions	60	(1)
References	61	(1)
Further reading	61	(2)
Efficacy	63	(34)
Introduction	63	(1)
The molecular nature of efficacy	64	(4)
Enrichment of receptor conformation by conformational selection	65	(1)
Conformational induction vs selection and energy landscapes	66	(2)
The concept of efficacy in receptor theory	68	(8)
Stimulus - response	69	(6)
Efficacy as a dimensionless proportionality factor	75	(1)
Negative efficacy and inverse agonists	76	(1)
Why measure efficacy?	77	(9)
Methods to quantify efficacy	86	(5)
The method of furchgott	86	(2)
Relative maximal responses	88	(2)
Efficacy measurements with binding studies	90	(1)
Agonist-selective receptor states: a possible tool for further selectivity	91	(2)
Limitations to efficacy as a drug parameter	93	(2)
Conclusions	95	(1)
References	95	(1)
Further reading	96	(1)
Pharmacological Assays used in Screening for Therapeutic Ligands	97	(38)
Introduction	97	(1)
Binding assays	97	(9)
Functional assays	106	(9)
Real-time, stop-time and historical assays	111	(4)
Ligands for orphan receptors	115	(8)
Screening orphan receptors with constitutive receptor assays	115	(5)
Construction of constitutive receptor assays	120	(3)
Constitutive activity and historical (reporter) assays	123	(1)
Secondary testing in specialized assays for ligand taxonomy	123	(3)
Human recombinant receptor systems	126	(5)
What is the optimal receptor density for different assays?	128	(1)
Function	128	(1)
Binding	129	(2)
References	131	(3)
Further reading	134	(1)
Finding the optimal assay format for the chemical target	135	(36)
About targets and target molecules	135	(2)
The definition of four type of allosteric ligand	137	(11)
What are allosteric ligands and why are they useful?	139	(6)
Screening for allosteric ligands	145	(1)
How can allosteric ligands be detected?	146	(2)
When binding and function do not agree	148	(4)
Matching the chemical and biological targets with a screening assay	152	(17)
Screening for agonists	154	(1)
Functional assays	154	(1)
Binding assays (agonist radioligand)	155	(3)
Binding assays (antagonist radioligand)	158	(1)
Screening for an antagonist	159	(1)
Binding assays	160	(5)
Functional assays	165	(1)
Constitutive receptor assays	165	(1)
Screening for inverse agonists	166	(1)
Constitutive receptor assays	166	(1)
Binding assays	167	(1)
Screening for allosteric enhancers	168	(1)
Conclusions	169	(1)
References	169	(2)
Mathmatical and Statistical Framework for Problems in Drug Discovery	171	(84)
Introduction	171	(1)
Fundamental principles of data analysis	171	(54)
Stating the research questions	173	(1)
Measurement scales	174	(1)
Populations and samples	174	(3)
Variability	177	(1)
Determining assay variability or precision	178	(3)
Measurements of central tendency and variance	181	(2)
Sampling theory	183	(2)
Sample distributions	185	(5)
Sample size estimation	190	(1)
Descriptive and inferential statistics	191	(2)
Hypothesis testing and t-tests	193	(5)
Analysis of variance	198	(8)
Repeated measures analysis of variance	206	(1)
Multiple tests	207	(3)
Non-parameteric statistics	210	(1)
Outliers	211	(6)
Resampling methods	217	(8)
Mathematical models	225	(17)
Model complexity	225	(1)
Data-fitting models and concentration-response curves	225	(1)
Simulation models	226	(1)
Caricature models	227	(1)
Heuristic models	227	(1)
Models of g-protein-coupled receptor systems	227	(1)
Regression and correlation	228	(11)
Model selection	239	(1)
Practical guidelines for fitting models to data	240	(2)
Data mining	242	(2)
Summary	244	(1)
References	245	(1)
Further reading	246	(1)
Code for combinatiorial library simulation	247	(1)
JMP formula to calculate power curves	248	(1)
Statistical formulae	248	(7)
Statistical Methods for Target Identification and Validation	255	(44)
Introduction	255	(1)
Principles of molecular genetics	256	(11)
Inheritance and definition of genetic terms	257	(1)
Genotypes and polymorphism	258	(2)
Recombination	260	(2)
Linkage disequilibrium and allelic association	262	(2)
The relationship between phenotype and genotype	264	(3)
Linkage analysis	267	(8)
Association analysis	275	(7)
Gene expression analysis	282	(5)
The human genome project	287	(3)
Single nucleotide polymorphisms	289	(1)
From genetic studies to target identification	290	(3)
Summary	293	(1)
References	294	(2)
Further reading	296	(2)
Web addresses for the human genome project	298	(1)
Experimental Design	299	(58)
Introduction	299	(1)
Principles of experimental design	300	(16)
Theoretical basis	303	(1)
Classical experimental designs	304	(1)
Nomenclature	304	(1)
Full-factorial designs	305	(1)
Fractional-factorial designs	306	(1)
Response surface modeling	307	(1)
D-optimal designs	307	(2)
Identification of factors and their levels	309	(2)
Assay variability and replication	311	(1)
Analysis and interpretation of experimental designs	311	(3)
Space-filling experimental designs	314	(2)
Experimental design for biochemistry	316	(20)
Optimization of a scintillation proximity assay	316	(1)
Variability	316	(1)
Signal-to-noise ratio	317	(1)
pKi trend	317	(1)
Summary	317	(3)
Optimization of a plate reader for a homogeneous time-resolved fluorescence assay	320	(12)
Optimal sampling and data analysis protocol for a radiologand binding assay	332	(4)
Automated experimental design	336	(1)
Experimental design for chemistry	336	(17)
Experimental design for reaction optimization	337	(5)
Experimental design to select substituents	342	(2)
Experimental design for selection --- of compounds and coverage of space	344	(9)
Summary	353	(1)
References	353	(2)
Further Reading	355	(2)
Analysis and Interpretation of Data	357	(44)
Introduction	357	(1)
Multivariate visualization	358	(13)
Graphical links between different data types	358	(3)
Compression and reduction of dimensionality	361	(1)
Encoding, filtering and smoothing	362	(3)
Modeling and visualization	365	(1)
Leverage plots	366	(1)
Flower plots	366	(3)
Probability distributions	369	(1)
Spreadplots	369	(2)
Statistical analysis of high-throughput screening data	371	(23)
Recursive partitioning	371	(1)
Performing an analysis	372	(1)
Reading the tree	372	(2)
Analysis of an example	374	(2)
Interaction detection	376	(1)
Non-linear activity	376	(1)
Applications and extensions	376	(1)
Neural networks	377	(1)
Architecture and implementation	377	(3)
Practical considerations and examples	380	(1)
Overfitting	380	(2)
Overtraining	382	(1)
Alternative architectures	382	(1)
Summary	383	(1)
Genetic algorithms	384	(1)
Theoretical basis	384	(3)
Practical considerations and examples	387	(2)
Summary	389	(1)
Interpretation of data from pools	389	(5)
Statistical guide posts	394	(2)
References	396	(2)
Further reading	398	(3)
Index	401