Chemical perspective discovery

Pearlman R S and K M Smith 1998. Novel Software Tools for Chemical Diversity. Perspectives in Dn Discovery and Design vols 9/10/ll(3D QSAR in Drug Design Ligand/Protein Interactions ar Molecular Similarity), pp. 339-353. 

Jacoby E, Schuffenhauer A, Addin P. (2004) The contribution of molecular informatics to chemogenomics. Knowledge-based discovery of biological targets and chemical lead compounds. In H Kubini, G Muller (eds), Chemogenomics in Drug Discovery — A Medicinal Chemistry Perspective, pp. 139-166. Wiley-VCH,Weinheim. 

Pearlman, R. S. and Smith, K. M. (1998) Novel software tools for chemical diversity. Perspectives Drug Discovery Design 9, 339-353. 

Readers may note three imique features in this text. First, there is a substantial discussion of chemical reactions of all elements and many of their compounds, a practice abandoned nowadays by most modem reference and handbooks. Second, analytical methods are presented for identification and measurement of practically all entries. In many instances, the method is based on my own research and experience. Third, a preparation method is given for all entries. For most compoimds, more than one preparative method is presented, covering both laboratory and commercial production. Also, a brief history of the discovery and early production of selected elements is presented to serve as backgroimd against which modern methods may be judged and historical perspective maintained. 

Evans, D.C., Watt, A.P., NicoD-Griffith, D.A. and Baillie, T.A. (2004) Drug-protein adducts an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chemical Research in Toxicology, 17 (1), 3—16. 

Provision 1 above, establishing a strategic alliance or collaborative relationship, is the most difficult to implement. In fact, few arrangements of this kind exist between fine-chemical companies and their customers. There are two main stumbling blocks. From the perspective of the fine-chemical company, it is the request of the customer to have the liberty to switch to other suppliers if these are able to grant better prices or other contractual terms. From the perspective of the customer, it is the desire of the fine-chemical companies to keep the intellectual property rights on discoveries that they make in the context of an alliance. This is especially the case if the customer is an ethical pharmaceutical company (see Chapter 14). 

The various topics discussed in this book have up to this point been arranged as far as possible on the basis of chemical structure compounds that contain one oxygen and one nitrogen atom have, for example, as a general rule preceded those that contain two nitrogen atoms. The fact that virtually all of the entities that follow show CNS activity combined with the circumstance that phenothiazines comprise a large part of this section require a departure from that approach. The serendipitous discovery of the antipsychotic activity of the phenothiazines in the early 1950s virtually opened the modern era of medicinal chemistry. These will thus be discussed at the outset to preserve historical perspective. 

Characterizing the hazards of new chemical entities is as much of an art as it is a science. As they are new, there is usually no information available on the specific compound, and it can be several months to years after the discovery of the new chemical entity before it can be well-characterized from a health and safety perspective. This is due to a number of reasons. First, enough of the compound needs to be synthesized so that there is a sufficient quantity available for testing and analysis. As the yields early on are quite small, it may take several syntheses before there is sufficient material for testing. Secondly, complete hazard characterization is expensive it is cost prohibitive to conduct extensive testing on every newly discovered compound. In addition, a vast percentage of new compounds will never become approved drugs. 

Quantitative structure-activity relationship (QSAR) models have proven their utility, from both the pharmaceutical and toxicological perspectives, for the identification of chemicals that might interact with ER. While their primary function in the pharmaceutical enterprise is lead discovery and optimization for high-affinity ER ligands, QSAR models can play an essential role in toxicology as a priority-setting tool for risk assessment. 

This chapter discusses several statistical mechanical theories that are strongly positioned in the historical sweep of the theory of liquids. They are chosen for inclusion here on the basis of their potential for utility in analyzing simulation calculations, and their directness in conneeting to the other fundamental topic discussed in this book, the potential distribution theorem. Therefore tentacles can be understood as tentacles of the potential distribution theorem. From the perspective of the preface discussion, the theories presented here might be useful for discovery of models such as those discussed in Chapter 4. These theories are a significant subset of those referred to in Chapter 1 as ... both difficult and strongly established. .. (Friedman and Dale, 1977), but the present chapter does not exhaust the interesting prior academic development of statistical mechanical theories of solutions. Sections 6.2 and 6.3 discuss alternative views of chemical potentials, namely those of density functional theory and fluctuation theory. 

It is helpful to contrast the view we adopt in this book with the perspective of Hill (1986). In that case, the normative example is some separable system such as the polyatomic ideal gas. Evaluation of a partition function for a small system is then the essential task of application of the model theory. Series expansions, such as a virial expansion, are exploited to evaluate corrections when necessary. Examples of that type fill out the concepts. In the present book, we establish and then exploit the potential distribution theorem. Evaluation of the same partition functions will still be required. But we won t stop with an assumption of separability. On the basis of the potential distribution theorem, we then formulate additional simplified low-dimensional partition function models to describe many-body effects. Quasi-chemical treatments are prototypes for those subsequent approximate models. Though the design of the subsequent calculation is often heuristic, the more basic development here focuses on theories for discovery of those model partition functions. These deeper theoretical tools are known in more esoteric settings, but haven t been used to fill out the picture we present here. 

---