Analitical techniques in combinatorial chemistryAuthor: Swarth M.E.
Publishers: Marcel Dekker
Year of publication: 2000
Number of pages: 311
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ANALYTICAL TECHNIQUES IN COMBINATORIAL CHEMISTRY
edited iiy Michael ? Swartz
ANALYTICAL TECHNIQUES IN COMBINATORIAL CHEMISTRY
edited by Michael E. Swartz
Waters Corporation Milford, Massachusetts
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Foreword: Chemistry Becomes an Information Science
Nothing in recent years has had as great an impact on the process of drug discovery as the rise of genomics and combinatorial chemistry. Nothing has been more urgently needed. In the United States today it takes an average of 13 years and over $300 million to develop a drug. Although regulatory hurdles account for a good portion of those costs, major difficulties lie in two other areas.
First, there are not enough drug targets. There are about 6000 known drugs, half of which hit human targets. However, those 3000 human-directed drugs hit only about 500 targets, which means that less than 1% of the human genome (estimated to contain 80,000 to 100,000 genes) has been exploited pharmaceutically. It’s even worse for antimicrobial drugs. Consider antifungal agents: almost every marketed antifungal agent hits one of a handful of targets in the same metabolic pathway. Genomics, the science of identifying and sequencing all of the genes in an organism, is changing all this at an astonishing rate. Soon we will have a plethora of targets, for pathogens and people. However, this only makes the second difficulty—that there aren’t enough drugs— more acute.
Those 6000 known drugs fall into only around 300 chemical classes (the exact figure depends on how one defines a ‘‘class’’). Recently, a major pharmaceutical company screened its entire compound inventory—over 400,000 compounds developed over almost 100 years of work—against a new target identified by genomics. They did not find a single hit. This sounds surprising until one examines that inventory closely: almost half the compounds in it could be considered to be derived from a single chemical class.
It is this problem that combinatorial chemistry is designed to solve, and its explosive growth is testimony to both the magnitude of the problem and
the early successes of the combinatorial approach. Combinatorial chemistry has many guises. In its purest form it involves the synthesis of all possible compounds from a set of modular building blocks. However, it can also mean high-throughput parallel synthesis of individual pure compounds, simultaneous synthesis of mixtures of compounds free in solution or on solid support, or a number of other variations on these themes. Regardless of the details of the process, the objective is the same: to produce a large number of chemically ‘‘diverse’’ compounds as rapidly as possible.
And that it does. Combinatorial methods have rewriten the standards for synthetic productivity. Until about 10 years ago, a good chemist could make and characterize perhaps 50 compounds per year. A combinatorial chemist aims for more like 50,000. Such numbers define a revolution, one that has already transformed the pharmaceutical industry and is likely to eventually make an impact on every other area of industrial chemistry. Analytical chemistry is no exception, which brings us to the subject of this splendid book.
It is, of course, one thing to make 50,000 compounds and quite another to know what one has made. Yet that is essential, because when new molecules are available in such staggering numbers chemistry has become an information science. Consider a chemically ‘‘diverse’’ (whatever that means, and nobody really knows yet) library of 50,000 compounds. Now screen that against, say, 50 different drug targets. Then imagine that you don’t know what any of the compounds are. The ones that give ‘‘hits’’ in your assays won’t remain unknown for long: you will purify those and characterize them. Yet in doing so, you will throw information away. If you knew the structure of every compound, then the ones that failed in your assays would be almost as valuable to you as the ones that succeeded because they would define the chemical types that were not likely to work for that particular set of target classes. Combinatorial chemistry promises to provide structure and activity data on a scale never before imagined, but it will do so only if one can characterize what one makes.