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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Presenting both a panoramic introduction to the essential disciplines of drug discovery for novice medicinal chemists as well as a useful reference for veteran drug hunters, this book summarizes the state-of-the-art of medicinal chemistry. It covers key drug targets including enzymes, receptors, and ion channels, and hit and lead discovery. The book hen surveys a drug's pharmacokinetics and toxicity, with a solid chapter covering fundamental bioisosteres as a guide to structure-activity relationship investigations.
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Seitenzahl: 494
Veröffentlichungsjahr: 2020
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Table of Contents
Cover
Preface
1 Drug Targets
1.1 Selection and Validation of Drug Targets
1.2 Enzymes
1.3 Receptors
1.4 Ion Channels
1.5 Carrier Proteins
1.6 Structural Proteins
1.7 Nucleic Acids
1.8 Protein-Protein Interactions
1.9 Further Reading
1.10 References
2 Hit/Lead Discovery
2.1 Irrational Drug Design (Serendipity)
2.2 Natural Products
2.3 High Throughput Screening (HTS)
2.4 Fragment-based Lead Discovery
2.5 DNA-encoded Library (DEL)
2.6 PROTAC
2.7 Further Reading
2.8 References
3 Pharmacokinetics (ADME)
3.1 Physicochemical Properties
3.2 Absorption
3.3 Distribution
3.4 Metabolism
3.5 Excretion
3.6 Prodrugs
3.7 Further Reading
3.8 References
4 Bioisosteres
4.1 Introduction to Bioisosteres
4.2 Deuterium, Fluorine, and Chlorine Atoms as Isosteres of Hydrogen
4.3 Alkyl Isosteres
4.4 Alcohol, Phenol, and Thiol Isosteres
4.5 Carboxylic Acid and Derivative Isosteres
4.6 Scaffold Hopping
4.7 Peptide Isosteres
4.8 Further Reading
4.9 References
5 Structural Alerts for Toxicity
5.1 Reactive Electrophiles
5.2 DNA Intercalators
5.3 Carcinogens
5.4 Metabolism Problematic Molecules
5.5 PAINS
5.6 Conclusions
5.7 References
Index
End User License Agreement
List of Tables
Chapter 1
Table 1.1. Selectivity of NSAIDS.
Chapter 2
Table 2.1 Ro3 and Ro5.
Chapter 3
Table 3.2. Estimation of volume distribution,
V
ss
(L/kg)
Table 3.3 Clearance, Cl (mL/min/kg).
Table 3.4 Half-life,
t
1/2
(h).
Table 3.5 Half-life values of 15 common drugs.
Table 3.6 Physiologic volumes of body fluids across nonclinical species and h...
Table 3.7 Volume of distribution (
V
d
) for acidic, neutral, and basic compound...
Table 3.8 Common drug-binding proteins.
Table 3.9 Approximation of plasma protein binding.
Table 3.10 Some representative drugs′ plasma protein binding.
79
Table 3.11 CYP450 3A4 and statin metabolism.
Table 3.12 Commercially available prodrugs and their solubility.
List of Illustrations
Chapter 1
Figure 1.1 The drug target quadrants.
Figure 1.2 The renin-angiotensin system (RAS).
Figure 1.3 Definition of binding sites for zinc-containing proteases and pro...
Figure 1.4 S
1
hydrophobic binding pocket inside ACE.
Figure 1.5 The function of protein kinases and phosphatases.
Figure 1.6 DPP-4 cleaves GLP-1 at the penultimate position from the N-termin...
Figure 1.7 Functions of DPP-4 inhibitors.
Figure 1.8 MEK1:AMP-PCP ternary complex co-crystal structure for
24
. Dash li...
Figure 1.9 Equilibrium of SHP2 in closed (blockade active site) and open (fr...
Figure 1.10 Dual allosteric inhibition of SHP2 phosphatase.
Figure 1.11 Warhead reactivity.
Figure 1.12 The structure of BTK. The C481S mutation in the kinase domain me...
Figure 1.13 Afatinib (
39
), a second-generation EGFR inhibitor, was designed ...
Figure 1.14 Roles of nitric oxide, cGMP, phosphodiesterase, and sildenafil (
Figure 1.15 G-Protein-coupled receptor with 7 trans-membrane domains.
Figure 1.16 Subtypes of serotonin receptors.
Figure 1.17 Subtypes of dopamine receptors.
Figure 1.18 The Hedgehog pathway.
Figure 1.19 PPAR-γ gene transcription mechanism and its biologic effects.
Chapter 3
Figure 3.1 Partition of a neutral molecule between 1-octanol (o) and water (...
Figure 3.2 Partition of an acid or a base between 1-octanol (o) and water (w...
Figure 3.3 Oral pharmacokinetics parameters.
Figure 3.4 FDA's Biopharmaceutical Classification System (BCS).
Figure 3.5 Transcellular absorption.
Figure 3.6 Absorption by active transport.
Figure 3.7 Physicochemical property space.
Figure 3.8 A drug's plasma protein binding.
Figure 3.9 Route of oral drugs.
Guide
Cover
Table of Contents
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Medicinal Chemistry for Practitioners
First Edition
Jie Jack Li
This edition first published copyright year
© copyright year John Wiley & Sons, Inc.
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Library of Congress Cataloging–in–Publication Data
Names: Li, Jie Jack, author.
Title: Medicinal chemistry for practitioners / Jie Jack Li.
Description: First edition. | Hoboken, NJ : Wiley, 2020. | Includes bibliographical references and index.
Identifiers: LCCN 2020001246 (print) | LCCN 2020001247 (ebook) | ISBN 9781119607281 (cloth) | ISBN 9781119607274 (adobe pdf) | ISBN 9781119607304 (epub)
Subjects: MESH: Chemistry, Pharmaceutical | Pharmaceutical Preparations–chemistry | Pharmacokinetics | Drug Delivery Systems | Drug Design
Classification: LCC RS403 (print) | LCC RS403 (ebook) | NLM QV 744 | DDC 615.1/9–dc23
LC record available at https://lccn.loc.gov/2020001246
LC ebook record available at https://lccn.loc.gov/2020001247
Cover design: Wiley
Cover image: © Egorov Artem/Shutterstock
Dedicated to Dr. Min Min Yang
Preface
This is a book that I wish I had when I became a medicinal chemist myself, fresh out of school with abundance of synthetic skills and little medicinal chemistry prowess. When I began my first medicinal chemistry job at Parke-Davis in 1997, I had to learn it “on the job”.
Prof. E. J. Corey once said: “The desire to learn is the greatest gift from God”. This message has resonated with me throughout my career in drug discovery and I tried to learn as much as I can. This book is the result from the “recrystallization’ of all these years of learning. Here, I want to thank my mentors: Bruce Roth and Sham Nikam from Parke-Davis/Pfizer; and Nick Meanwell at BMS. I am also indebted to my fellow medicinal chemists whose papers, reviews, books, and conference presentations are cited throughout this manuscript.
I hope this book will be a good starting point for novice medicinal chemists and veteran medicinal chemists find it useful as well.
As always, I welcome your critique. You could email me your comments directly to: [email protected].
Jack LiNov. 1, 2019San Mateo, California
