Pharmacology in Drug Discovery

Understanding Drug Response

Terry P. Kenakin, Terry Kenakin

• Publisher: Academic Press
• Year: 2011
• eBook ISBN: 9780123848574
• Topic: Medicine
• Subtopic: Pharmacology

Pharmacology in Drug Discovery: Understanding Drug Response is designed for all students, recent graduates, and new researchers in the pharmaceutical and biotechnology industries who need to interpret change in physiology induced by a chemical substance. Physiological systems customize chemical signal input to their own needs; therefore the same drug can have different effects in different physiological systems. The field of pharmacology is unique in that it furnishes the tools to analyze these different behaviors and traces them to their root cause. This enables predictions of drug behavior to be made in all systems, an invaluable tool for drug discovery because almost all drugs are developed in test systems far removed from the therapeutic one. This valuable resource provides simple explanations of the ways in which biological systems use basic biochemical mechanisms to produce fine chemical control of physiology, allowing for more informed predictions of drug effects in all systems and forming the basis of the drug-discovery process. Chapters follow a logical progression on how to characterize the pharmacology of any given molecule, and include important terminology, chapter summaries, references, and review questions to aid the reader in understanding and retention of the material.- Enables the reader to interpret drug dose-response data and make mechanistic inferences at the molecular level- Bridges the gap between biochemistry and therapeutic medicine- Chapters include key topics such as drug affinity and efficacy, enzymes as drug targets, in vivo pharmacology, safety pharmacology, and more

Chapter 1. Pharmacology

The Chemical Control of Physiology

Outline

Pharmacology and Cellular Drug Response1

New Terminology2

Pharmacological Targets2

Dose–Response Curves5

Linking Observed Pharmacology With Molecular Mechanism12

Descriptive Pharmacology: I15

Summary16

This chapter discusses how drug response is quantified with dose–response curve and how this leads to classifications of drugs based on effect (i.e., drugs that produce observed change in cellular processes are termed agonists and those that block such effects are antagonists). The dependence of observed potency of an agonist upon two drug-related parameters (affinity, efficacy) and two cell-dependent parameters (target density and efficiency of target coupling) is also discussed. The way that different tissues process drug stimulus to provide tissue response is considered, along with the null method which can be used to negate cell-dependent effects on drug activity to provide system-independent indices of drug activity. This is imperative in pharmacology as drugs are almost always studied in test systems, and not in therapeutic one(s).

Keywords

affinity, agonists, antagonists, dose–response curves, efficacy, null method, potency.

By the end of this chapter the reader should be able to understand how drug response is quantified by the use of dose–response curves, the way in which different tissues process drug stimulus to provide tissue response and what qualifies a drug to be classified either as an agonist or antagonist.

Pharmacology and Cellular Drug Response

Pharmacology (from the Greek φάρμακον, pharmakon, “drug” and -λογία, -logia, the study of) concerns drug action on physiological systems (physiology from the Greek φύσις, physis, “nature, origin” and -λογία, -logia is the study of the mechanical, physical and biochemical functions of living organisms). With regard to the application of pharmacology to the discovery of drugs for therapeutic benefit, the main focus of pharmacological theories, procedures and mechanisms relates to the chemical control of physiological processes. Insofar as the understanding of these physiological processes benefits the pharmacologic pursuit of drugs, pharmacology and physiology are intimately related. However, it will also be seen that complete understanding of the physiologic processes involved is not a prerequisite to the effective use of pharmacology in the drug discovery process. In fact, often an operational approach is utilized whereby the complexity of the physiology is represented by simple surrogate mathematical functions.

A unique feature of pharmacology is that the effect of the drug is often observed indirectly, that is, while the drug affects a select biochemical process in the cell, the outcome to an observer is an overall change in the state of the whole organism, and this is often the result of multiple interacting cellular processes. A major aim of pharmacology is to define the molecular events in initiating drug effects, since these define the action of drugs in all systems. If quantified correctly, this information can be used to predict drug effect at the pharmacological target in all systems including therapeutic one(s). At this point, it is useful to define what is meant by pharmacological target.

New Terminology

The following new terms will be introduced in this chapter:

• Affinity: The propensity of a drug molecule to associate closely with a drug target.

• Agonists: Drugs that produce an observable change in the state of a physiological system.

• Antagonists: Drugs that may not produce a direct effect, but do interfere with the production of cellular response to an agonist.

• Dose–response curve: The relationship between doses (if the drug is used in vivo) or concentrations (if used in vitro) of a drug and pharmacologic effect.

• Drug target: The protein (or in some cases DNA, mRNA) to which a drug binds to elicit whatever pharmacologic effect it will produce. These proteins can be seven transmembrane (or one transmembrane) receptors, enzymes, nuclear receptors, ion channels or transport proteins.

• EC₅₀: Concentration of agonist producing half the maximal response to the same agonist; usually expressed for calculation and statistical manipulation as the pEC₅₀, negative logarithm of the molar concentration producing 50% response.

• Efficacy: The change in state of the drug target upon binding of a drug.

• Efficiency of target coupling: The relationship between the net quanta of activation given to a cell and the number of drug targets available for activation.

• Full agonists: Agonists that produce the full maximal response that the system can produce.

• Null method: The comparison of equiactive concentrations (or doses) of drug to cancel the cell-based processing of drug response. The assumption is that equal responses to a given agonist are processed in an identical manner by the cell.

• Partial agonists: Agonists that produce a maximal response that is of lower magnitude than the maximal response that the system can produce to maximal stimulation.

• pEC₅₀: The negative logarithm of EC₅₀ values. For arithmetic and/or statistical manipulation, numbers must be normally distributed. This is true only of pEC₅₀s, not of EC₅₀s; thus all averages, estimates or error and statistical procedures must use pEC₅₀.

• Potency: The concentration (usually molar) of drug needed to produce a defined response or effect.

• Target density: The concentration of drug targets at the site of activation, i.e., on the cell surface for receptors.

Pharmacological Targets

The term “pharmacological target” refers to the biochemical entity to which the drug first binds in the body to elicit its effect. There are a number of such entities targeted by drug molecules. In general, they can be proteins such as receptors, enzymes, transporters, ion channels, or genetic material such as DNA. The prerequisite for pharmacologic targets is that they have the ability to discern differences in electronic structure minute enough to be present in small drug-like molecules; in this regard the most predominant targets for drugs are protein in nature. Proteins have the tertiary three-dimensional structure necessary for detailed definition of the electronic forces involved in small molecule binding. Signals are initiated through complementary binding of drug molecules to protein conformations that have a physiological purpose in the cell. The act of these molecules binding to the protein will change it, and with that change a pharmacologic effect will occur.

At this point, it is worth considering the beginning and end processes. The first process is the drug binding to the target. The result(s) of this process are totally dependent on the af...

Table of contents

• Cover image
• Table of Contents
• Front-matter
• Copyright
• Dedication
• Foreword
• Acknowledgements
• Chapter 1. Pharmacology
• Chapter 2. Drug Affinity and Efficacy
• Chapter 3. Predicting Agonist Effect
• Chapter 4. Drug Antagonism
• Chapter 5. Allosteric Drug Effects
• Chapter 6. Enzymes as Drug Targets
• Chapter 7. Pharmacokinetics I
• Chapter 8. Pharmacokinetics II
• Chapter 9. In Vivo Pharmacology
• Chapter 10. Safety Pharmacology
• Appendix A. Answers to Chapter Questions
• Appendix B. Derivations and Proofs
• Index