Biomedical Engineering Reference
In-Depth Information
Introduction to Drug
Design and Discovery
Povl Krogsgaard-Larsen and Lennart Bunch
CONTENTS
I.1 Medicinal Chemistry—An Interdisciplinary Science ............................................................ 1
I.2 Drug Discovery—A Historical Perspective............................................................................ 2
I.3 Therapeutic Targets—Identii cation and Validation............................................................... 4
I.4 The Drug Development Process—An Outline ....................................................................... 5
I.5 Discovery of Drug Candidates................................................................................................ 6
I.5.1 Natural Products—Role in Target Identii cation ....................................................... 6
I.5.2 Natural Products as Lead Structures ......................................................................... 7
I.5.3 Basic Principles in Lead Development and Optimization ......................................... 9
I.5.3.1 Bioisosterism ............................................................................................ 10
I.5.3.2 Stereochemistry........................................................................................ 10
I.5.3.3 Membrane Penetration—Including Lipinski Rule of Five....................... 12
I.5.3.4 Structure-Based Drug Design .................................................................. 12
I.6 Individualized Medicine and Concluding Remarks ............................................................. 13
Further Readings .............................................................................................................................. 13
I.1 MEDICINAL CHEMISTRY—AN INTERDISCIPLINARY SCIENCE
Therapeutic agents are chemicals that prevent disease, assist in restoring health to the diseased, or
alleviate symptoms associated with disease conditions. Medicinal chemistry is the scientii c dis-
cipline that makes such drugs available through either discovery or design processes. Throughout
history, drugs were primarily discovered by empirical methods, investigating substances or prepa-
rations of materials found in the local environment. Over the previous centuries, chemists devel-
oped methods and techniques for the isolation and purii cation of the active principles in medicinal
plants. The purii cation and structure determination of natural products like morphine, hyoscy-
amine, quinine, and digitalis glycosides represent milestones in the i eld of drug discovery and the
beginning of medicinal chemistry as a fascinating independent i eld of research (Figure I.1).
In the twentieth century, a very large number of biologically active natural products were
structurally modii ed in order to optimize their pharmacology, and novel drugs were prepared
by use of increasingly advanced synthetic methods. Moreover, the rapidly growing understanding
of the nature of disease mechanisms, how cells function, and how drugs interact with cellular
processes has led to the rational design, synthesis, and pharmacological evaluation of new drug
candidates. Most recently, new dimensions and opportunities have emerged from a deeper under-
standing of cell biology and genetics.
Modern medicinal chemistry draws upon many scientii c disciplines, organic and physical
chemistry being of fundamental importance. But other disciplines such as biochemistry, molecu-
lar biology, pharmacology, neurobiology, toxicology, genetics, cell biology, biophysics, physiology,
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