The Tools of Medicinal Chemistry

In 1982 Ayerst Laboratories in Montreal became the first company in Canada to install a commercial software tool (the SYBYL suite from Tripos Associates) to help in the development of pharmacophoric models from structure-activity relationships. The installation of the software was the second ever, worldwide, by a company and is a testimonial to the foresight of the director of medicinal chemistry, Dr. Leslie Humber, for having championed its installation. Dr. Adi M. Treasurywala, then an organic chemist with some experience in medicinal chemistry, became the first industrial computational chemist in Canada that year. The use of modeling approaches contributed in a minor but significant way to the discovery of the compound known as Tolrestat, which was an inhibitor of lens aldose reductase. This led to the acknowledgment of Treasurywala as a coinventor of the drug on several patents that were filed in this research area. Approximately in 1983, Ayerst closed down its discovery effort in Canada and moved to Princeton, New Jersey, where an expanded effort in the area of computational chemistry continues. 

Both examples reported above suggest that the pharmacophoric approach provided by Catalyst could represent a useful and efficient tool available to modelers working in the field of medicinal chemistry. However, it is necessary to em-... 

The treatment of malaria infections holds a venerable place in the history of medicinal chemistry and of natural product chemistry. As commonly well-known, the first specific treatment for malaria dates back to the 17th century when the bark of Cinchona trees was used as the best tool to face infections of malaria, that was endemic in Africa, Asia but also in several parts of Europe and North America. Later, malaria was the first disease to be treated with an active principle isolated from a natural source, quinine [(1), Fig. (1)] isolated from the Cinchona bark in 1820, and, later again, the first human disease to be treated with a synthetic drug (methylene blue in 1891). 

In conclusion, it became evident to the physicists that the concept of isosterism, developed before quantum-mechanical theories, could not provide at the molecular level the same results as those that the periodic classification had provided for the elements, namely a correlation between electronic structure and physical and chemical properties. In the field of medicinal chemistry the isosterism concept, taken in its broadest sense, has proved to be a research tool of the utmost importance. The main reason for this is because isosteres are often much more alike in their biological than in their physical and chemical properties. An illustrative example is found in the comparison of oxazolidine-diones and hydantoins which possess different chemical reactivities, but present a similar antiepileptic profile (Fig. 13.2). 

In the field of medicinal chemistry, scientists identify, synthesize, develop, and study chemicals to use for diagnostic tools and pharmaceuticals. Pharmacology is the study of how chemical substances interact with living systems. As biological knowledge has increased, the biochemical causes of many diseases have been determined and the field of pharmacology has grown tremendously. 

The ability of small molecules to interact with biological macromolecules such as proteins in a selective, often reversible, and dose-dependent manner, and to exert specific effects, has led to them being regarded as powerful tools for the study of biological systems. The use of small molecules in this manner to selectively perturb biological function underpins the whole of medicinal chemistry as well as forming the basis for the field of chemical genetics. ... 

The HINT software is available from Haney Associates, 12010 Medoc Lane, San Diego, CA 92131, as a tool interfaced with the SYBYL package. http //www.i2020.net/edusoft/haney/haney.html The use of the molecular lipophilicity potential to predict virtual log P and to add a lipophilicity field to the CoMFA method can be performed by using the CLIP software available from the Institute of Medicinal Chemistry, University of Lausanne, BEP, CH-1015 Lausanne, Switzerland. http //www.unil.ch/pharm/clip/... 

Here we discuss some of the important problems in biology and medicine being tackled with the tools of physical chemistry. We shall see that physical chemists contribute importantly not only to fundamental questions, such as the unravelling of intricate relationships between the structure of a biological molecule and its function, but also to the apphcation of biochemistry to new technologies. 

Parallel synthesis has become an increasingly important tool for the optimization of medicinal chemistry leads. We have established a centralized parallel synthesis/purification team that collaborates with medicinal chemistry program groups for this purpose. The goal is to quickly provide substantial SAR to these teams in order to enable rapid decision making and iterative exploration of interesting chemotypes. Lean manufacturing concepts have been employed to optimize our processes and increase efficiency. We will describe the evolution of our process and lessons learned over the past two years. 

Nobel-laureate Richard Feynman once said that the principles of physics do not preclude the possibility of maneuvering things atom by atom (260). Recent developments in the fields of physics, chemistry, and biology (briefly described in the previous sections) bear those words out. The invention and development of scanning probe microscopy has enabled the isolation and manipulation of individual atoms and molecules. Research in protein and nucleic acid stmcture have given rise to powerful tools in the estabUshment of rational synthetic protocols for the production of new medicinal dmgs, sensing elements, catalysts, and electronic materials. 

Bioisosteric relations constitute one of the more familiar tools in medicinal chemistry. There are thus sets of atoms that can often be interchanged without much... 

It is worth noting that the past few years have witnessed tremendous development of web-based information resources. Notably, the PubMed search tool [4] has made the investigation of any life sciences topic much easier. It offers keyword and author (as well as structure and sequence) searches and covers a wide range of medicinal chemistry-related journals. This resource, coupled with e-journals, affords the medicinal chemist the tools to keep up with any research topics of interest. Because of the public nature of the Web, now a chemist can sometimes find critical journal articles on the Web that do not show up until much later in traditional literature sources. It is not uncommon that scientific meeting presentations can be found on the Web. Indeed, the Internet tools we have all become familiar with also have made the professional life of the medicinal chemist much easier. 

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