Structure-based Design of Drugs and Other Bioactive Molecules

Tools and Strategies

Arun K. Ghosh, Sandra Gemma

• Publisher: Wiley-VCH
• Year: 2014
• Print ISBN: 9783527333653
• eBook ISBN: 9783527665235
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

Drug design is a complex, challenging and innovative research area. Structure-based molecular design has transformed the drug discovery approach in modern medicine. Traditionally, focus has been placed on computational, structural or synthetic methods only in isolation. This one-of-akind guide integrates all three skill sets for a complete picture of contemporary structure-based design. This practical approach provides the tools to develop a high-affinity ligand with drug-like properties for a given drug target for which a high-resolution structure exists. The authors use numerous examples of recently developed drugs to present "best practice" methods in structurebased drug design with both newcomers and practicing researchers in mind. By way of a carefully balanced mix of theoretical background and case studies from medicinal chemistry applications, readers will quickly and efficiently master the basic skills of successful drug design. This book is aimed at new and active medicinal chemists, biochemists, pharmacologists, natural product chemists and those working in drug discovery in the pharmaceutical industry. It is highly recommended as a desk reference to guide students in medicinal and chemical sciences as well as to aid researchers engaged in drug design today.

1
From Traditional Medicine to Modern Drugs: Historical Perspective of Structure-Based Drug Design

1.1 Introduction

The drug design and discovery process of today is a highly interdisciplinary research endeavor [1–3]. Advances in molecular biology, synthetic chemistry, and pharmacology, as well as technological breakthroughs in X-ray crystallography and computational methods have brought dramatic changes to medicinal chemistry practices during the late twentieth century. Drug design efforts based upon the three-dimensional structure of a target enzyme have become the hallmark of modern molecular design strategies. This structure-based design approach has revolutionized the practice of medicinal chemistry and recast the preclinical drug discovery process. Many of the FDA-approved drugs have evolved through structure-based design strategies. By 2012, as many as 35 newly approved drugs have emanated from structure-based design. The post-genomic era holds huge promise for the advancement of structure-based design of drugs for new therapies. Human genome sequencing has now revealed that there are an estimated 20,000–25,000 protein-coding human genes, and each gene can code for one protein. These proteins are responsible for carrying out all the cellular functions in the human body. These proteins can also be involved in disease pathologies, providing unique opportunities and challenges for structure-based design of new drugs. It may be appropriate to review briefly how the first half of the twentieth century was shaped and enriched by a number of seminal discoveries and the advent of new technologies, all of which left an important imprint on today's drug discovery and medicinal chemistry. A number of previous reviews have provided some insight [4,5].

1.2 Drug Discovery During 1928–1980

The history of medicinal chemistry is marked by examples in which the discovery of novel drugs relied upon serendipity and clinical observations. It is interesting to consider the role of chance in unexpected and accidental scientific discoveries. This serendipity is not simply luck. Rather, it is a process of finding significance and value in the lucky coincidence. As Pasteur observed, “Chance favors the prepared mind.” Without engaging creative thinking and analysis, accidents do not lead to discoveries. The discovery of penicillin is a famous example of serendipity [6,7]. Alexander Fleming departed for a vacation in the summer of 1928. He left a bacterial culture of Staphylococcus aureus on his laboratory bench. When he returned a month later, he found that the culture was contaminated by a patch of blue-green mold that caused the lysis of bacteria. Fleming later demonstrated that the mold, Penicillium notatum, produced an active ingredient that he called penicillin. The discovery of penicillin was particularly fortunate since the penicillin that landed on Fleming's bacterial culture was not ordinary Penicillium! If it were, it would not have produced penicillin in high enough concentrations to cause the lysis of bacteria.

The discovery of penicillin was not mere luck. Much more subsequent investigation was required before it could be used as an antibiotic. More than a decade later in the 1940s, Howard Florey and Ernest Chain, with their Oxford team, unveiled its therapeutic potential. During this time, fermentation methods were developed that allowed the effective application of penicillins (Figure 1.1) for the treatment of bacterial infections in humans. Bactericidal penicillin rapidly replaced the bacteriostatic sulfonamide drugs used until then for the treatment of some bacterial infections.

Figure 1.1 Structures of penicillins G and V and semisynthetic penicillins.

The discovery of bacteriostatic sulfonamides has its own interesting story of serendipity and intuition [8]. The dye industry was advanced and promoted chemical manufacturing to develop new dyes. German chemists working with azo dyes observed that certain dyes could preferentially stick to and stain bacterial colonies. Could this serve as a way to target bacteria? In 1935, the German biochemist Gerhard Domagk, assisted by a group of chemists, synthesized and tested hundreds of dyes and finally discovered, by a trial-and-error approach, the potent antibacterial activity of Prontosil rubrum (Figure 1.2). Subsequent studies revealed that the active moiety of the compound was the 4-aminobenzenesulfonamide moiety. Introduction of substituents at both the p-aniline and the sulfonamide groups led to the development of new sulfanilide derivatives with broad-spectrum activity, improved pharmacokinetic properties, and lowered therapeutic side effects. The synthesis of new derivatives became less important due to the discovery and introduction of penicillin and subsequently discovered antibiotics.

Figure 1.2 Structures of prontosil and its derivative.

Research on sulfonamide derivatives, however, continued. Close observation of side effects led to the development of new uses and expansion of this class of compounds. The clinical observation that sulfa drugs induced hypoglycemia was followed by studies aimed at maximizing this side effect and dissociating it from the bacteriostatic activity. This led to the advent of oral hypoglycemia drugs for the treatment of diabetes. In 1940, Mann and Keilin discovered the inhibitory activity of sulfanilamide against carbonic anhydrase. This key discovery paved the way for the subsequent development of diuretic sulfonamides [9].

The discovery of the antidepressant agent iproniazid is also due to the clinical observation of a “side effect” [10]. Both isoniazid (Figure 1.3) and its isopropyl-substituted derivative iproniazid were originally developed as tuberculostatic drugs. However, it was observed that in contrast to isoniazid, patients treated with iproniazid experienced elevation of mood. Subsequent studies clarified that the antidepressant activities of iproniazid were due to the inhibition of the centrally active enzyme monoamine oxidase (MAO). Iproniazid was approved in 1958 for the treatment of depression. There are also more recent examples of clinical observations leading to the discovery of new drugs. Sildenafil or Viagra, a drug used for the treatment of erectile dysfunction, was originally developed for the treatment of angina [11,12]. Minoxidil [13,14], originally developed as an antihypertensive agent, was later approved for the treatment of hair loss.

Figure 1.3 Structures of isoniazids, minoxidil, and sildenafil.

Serendipity also played a role in the discovery of Librium, the first antianxiety benzodiazepine, but it did not happen by accident [15,16]. In 1954, Dr. Leo Sternbach was actively involved in the development of new tranquilizers in the New Jersey laboratories of Hoffmann-La Roche. He decided to explore the chemistry of benzheptoxdiazines, a class of compounds he had synthesized 20 years ago in search of new dyes but whose biological activity was unknown. His research group synthesized 40 new derivatives and determined that they were six-membered ring compounds such as 11 and 12 (Figure 1.4) rather than seven-membered ring compounds 13 and 14, as was originally thought. Pharmacological testing showed thes...

Table of contents

• Cover
• Related Titles
• Title Page
• Copyright
• Preface
• Chapter 1: From Traditional Medicine to Modern Drugs: Historical Perspective of Structure-Based Drug Design
• Part One: Concepts, Tools, Ligands, and Scaffolds for Structure-Based Design of Inhibitors
• Part Two: Structure-Based Design of FDA-Approved Inhibitor Drugs and Drugs Undergoing Clinical Development
• Index
• End User License Agreement