Tackling Medicinal Chemistry

In science, books tend to serve the purpose of bringing readers up-to-date on the existence of a growing information base in some particular field. The situation is quite different in the social sciences and humanities, where key books actually create large trends and become the focus of paradigm shifts in the intellectual thought process. It is my contention that the book "Molecules and Medicine" by Elias J. Corey, Barbara Czakó, and László Kürti, will, in fact, transcend informational value and serve to organize progress in its field, which is drug discovery and, more broadly, molecular medicine. Corey is an emeritus professor of chemistry at Harvard University and the 1990 Nobel Laureate in Chemistry. In Corey's group, Czakó is a postdoctoral fellow and Kürti is a Damon Runyon Cancer Fellow.

The book does not provide radical new breakthroughs in the biological or medical sciences. That is not its mission. The need it addresses, and it is a very large need, is that of bringing together the extraordinarily diverse elements of molecular medicine into an interactively manageable form. Remarkably, "Molecules and Medicine" succeeds in collecting, under one tent, a wide range of medical phenomenology extending from, for instance, anti-AIDS strategies and treatments to reproductive medicine.

One huge impediment to progress in the medicinal chemistry field has been the seemingly endless reach of its interests. For those who like to enter a field already armed with a sound grasp of the scope of its aspirations, medicinal chemistry represents a difficult and even forbidding challenge. This is because of the multifaceted and seemingly unfocused panorama that medicinal chemistry and pharma-based chemistry seek to encompass. Also constraining progress is the fact that medicinal chemistry depends to such a large extent on other sciences. A particularly key one of these is organic chemistry. Hence, for those who lack literacy in organic chemistry, substantive progress in understanding molecular medicine is correspondingly impeded. It is the bold willingness to undertake the whole expanse of molecular medicine that makes "Molecules and Medicine" so very special.

It's interesting to consider the backgrounds of the authors at the level of book writing. Corey previously coauthored an influential book, "Logic of Chemical Synthesis." Czakó and Kürti coauthored an excellent book, "Strategic Applications of Named Reactions in Organic Synthesis." The subject matters of those books are quite different from the current one. However, those books foreshadow the key ingredients of "Molecules and Medicine", conciseness of language, a strictly maintained focus, and clear adherence to priorities.

In fact, the authors wisely did not clutter "Molecules and Medicine" with accounts of the synthesis of drugs. Tempting as that may have been, particularly to Corey, a seminal historic leader in chemical synthesis, such an undertaking would have drawn the reader into admittedly critical, but still wholly different, terrain. In the end, the book is about drug discovery and drug usage, not synthesis.

This focus on drug discovery and drug usage is maintained throughout with remarkable consistency. The most noteworthy feature of the book is that, in a relatively limited space—272 pages, including many illustrations and an excellent index—the authors walk the reader through the dominant issues that have driven pharmaceutical science for the past century. They do this in what amounts to a series of position papers that describe particular fields in pharmaceutical science—for instance, infectious diseases, oncology, autoimmunity, and analgesia.

The descriptions of these fields include clear statements, which can be traced back to their origins, about the scope of the problem, the history of progress, and the major advances up to the present time. Each one- to two-page historiography also takes the reader through the key drugs that have made it at least to the clinic and more often through to registration. A brief history of each drug, including date of discovery and date of introduction, is provided. On each page, key references are provided. And at the end of each section, a much more complete bibliography brings the reader right up to the current state of the art.

Before launching into the case histories of particular medicinal chemistry fields, however, Part I of the book begins with an attempt to relay the principles of organic chemistry, and particularly of structural organic chemistry, to the reader. Issues such as nomenclature, a rough description of hybridizations, bonding, and a review of some key functional groups, are provided. From there, the crash course in organic chemistry goes into more sophisticated areas such as the structure of aromatic systems, models for π delocalization, and even introductory molecular orbital presentations. Given the importance of heterocyclics in providing molecules of value to medicinal chemistry, a short presentation of some of the more common ring systems is conveniently provided.

From there, still in Part I, the book goes on to teach issues of stereochemistry, including tetrahedral stereochemistry as well as olefin stereochemistry. The reader is rapidly exposed to a hierarchy of increasingly complex chemical structure information such that he or she can more fully appreciate the structure of a molecule like prednisone when it is presented by the authors. The introductory section ends with a preliminary discussion of some of the proteogenic amino acids and, remarkably, makes its way into polypeptide structures including visual notations to simplify perception. Part I even takes up some quite complex but medicinally important proteins with medicinally important ligands inserted into active sites.

This introduction to organic chemistry serves several purposes: Hopefully, it succeeds in whetting the appetite of readers who might have had one year of college-level organic chemistry or even a year of sophisticated high school chemistry. But it also prepares the reader for the chemical information that follows in the book. For senior chemists, the introduction could be useful for brushing up on ideas they don't necessarily use every day. However, it is not a freestanding treatment of organic chemistry, and readers who want to pursue the subject at a more meaningful level will be obliged to consult more extensive texts.

With the chemistry-level vocabulary and framework for the rest of the book established, in the chapters that follow, the reader experiences a kaleidoscopic guided tour of the major classical and contemporary topics in medicinal chemistry and their application to the fashioning of important drugs and medical treatments. For instance, in short order, the reader is taken on a guided tour of inflammation and cardiovascular diseases, metabolic diseases, as well as diabetes and hypercholestemia, ending with some useful introductory remarks on receptors and signaling. Continuing the broad survey of the field of medicinal chemistry, the reader is taken through a whirlwind of subfields such as reproductive medicine, osteoporosis, and autoimmune diseases.

The infectious diseases section is nicely subdivided among indications that call for antibiotics, antiviral agents, and antifungal agents. The chapter culminates in a particularly strong focus on antiparasitic agents. From there, the reader is taken to problems and advances in cancer chemotherapy. "Molecules and Medicines" ends with a strong chapter on central-nervous-system-related topics.

Remarkably, these terse descriptions of key subfields in medicinal chemistry cut to the heart of the matter. The high information content of the prose, the power of the illustrations, and the aptness of the referencing are actually overwhelming. The beauty of the book is that it does not get bogged down in details, critical though they are. Through the lenses of the history of medical science, biochemistry, cell biology, and structural biology—all in sync with the overarching rules of organic chemistry—the essential picture as to how the molecules of medicine came about emerges.

Fortunately, the discussions and the references allow the motivated reader to study the case histories in detail. "Molecules and Medicine" also has terrific information retrieval value, beautifully serving varying needs ranging from those of pharma name droppers to emerging scholars of the subject. The reader can trace, by common name, technical name, or trade name, almost any valuable drug out there and quickly track its history.

In summary, I predict that "Molecules and Medicine" will be kept close at hand by all students of pharma and even by many physicians and other health management personnel. In that sense, it will serve the purpose of not only informational value but also attracting new legions of enthusiastic believers to the promise of pharmaceutical sciences. That is clearly one intention of the authors.

With "Molecules and Medicine" conveniently nearby, I was unable to resist the opportunity for continuous browsing. The book presents virtually every drug that ever mattered and matters. I couldn't help but notice the remarkable influence that small-molecule natural products had in the development of valuable drugs. This impact includes drugs composed of natural products per se, derivatives synthesized from natural products, and structures clearly inspired by small-molecule natural products.

Correspondingly, I couldn't help but notice the role of happenstance and even serendipity in the drug discovery process. No one can read "Molecules and Medicine" and not take note that, historically, discoveries of the great drugs have benefited from a high level of intuition and plain good fortune.

In the fullness of time, the process of drug discovery will undoubtedly be less beholden to chance factors and more driven by the emergence of an increasingly crisp, logical science. That process will take some time, however. Unfortunately, in the lengthy interim, it would be tragic if the practitioners of pharmaceutical science and, indeed, the leaders of its management structure were so enamored of the presumed rationality of current pharmaceutical research as to undercut chances for spontaneous discovery.

I fear that the growing overreliance on the form of a discovery and the style of its packaging, rather than its inherent worth, may be responsible for some of the arthritic pipelines of big pharma today. I can't help but wonder if the Gettysburg Address would have attracted much attention these days, lacking the advantage of a slick PowerPoint presentation. More to the point, and more sobering, how would penicillin have fared had the initial discovery occurred in 2007 in the absence of a clearly defined molecular target against which were screened a mind-numbing collection of low-pedigree samples (often of questionable purity)?

This personal apprehension about the state of pharma research today notwithstanding, "Molecules and Medicine" was a joy to read and is an already critical part of the references I keep handy on my desk. It's a book that will inspire the field. In that sense, it not only reports on a scientific subject but also creates new dimensions. Bravo to authors Corey, Czakó, and László Kürti.