Modern Drug Discovery

It was very time-consuming to screen substances in animal tests for efficacy and to prepare lead analogues by classical synthesis. Therefore, it is not surprising that the researchers looked for alternatives. Today pharmaceutical companies apply computerized robotic systems in drug discovery. The starting point is the chemical library. This library does not contain books, but chemicals. Many companies keep small samples of all chemical compounds that they ever synthesized or extracted from the plant material. The amount of the samples is usually small and they are kept in microplates in dedicated temperature-controlled storage facilities. Chemical libraries of large pharmaceutical companies contain several million different compounds. 

The reaction between amino acid esters, 7, and aldehydes, 8, may serve as an example of a real combinatorial reaction that was used to produce 126 N-alkylated-a-amino methyl esters 10 via the intermediate 9. The identity and yield of the products were determined by LC-MS analysis [4], 

The relationship between chemical structure and activity has been recognized from early on, as the examples in Sec. 10.3.2 illustrate. Tbday, computerized expert systems allow the virtual screening of millions of possible structures with the objective to find the best candidates for development. However, the accuracy of such in-silico predictions is still low and it will take time before they can replace experimental discovery methods. 

To find a good assay for the desired pharmaceutical target is the critical step for successful HTS. Let us take a protein as an example for a target. Only substances that bind to protein can have physiological activity they provide a hit. Substances that do not bind fail the test and are no longer considered for this application. 

Screening a million compounds usually results in a few thousand hits. These hits are investigated further to either confirm their activity or eliminate false positives. At the end of the screening part a few promising candidates are selected as leads for further development. 

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Akritopoulou-Zanze I (2006) The identification of new protein kinase inhibitors as targets in modern drug discovery. ID rugs 9 481-487... 

Figure 3.2 Modern drug discovery and development processes.

In modern drug discovery speed and cost control are important in addition to high quality. In silica virtual screening for drugability [159] is a good first step in library... 

One very important aspect in modern drug discovery is the preparation of so-called substance libraries from which pharmaceutical lead structures might be selected for the treatment of different diseases. An efficient approach for the preparation of highly diversified libraries is the development of multicomponent reactions, which can be defined as a subclass of domino reactions. One of the most... 

Strohl, W.R. (2000) The role of natural products in a modern drug discovery program. Drug Discovery Today, 5, 39-41. 

The importance of physical properties in drug action underlies many aspects of modern drug discovery in particular, compound lipophilicity (as estimated by LogP, the logarithm of the 1-octanol-water partition... 

Schmidt, C.W., "Cashing in on Gene Sequences," Modern Drug Discovery, 4, 73-74 (May 2001). 

Hart, C. (1999). Getting past the politics and paperwork of pediatric drug studies. Modern Drug Discovery 2 15-16. 

Lead optimization of new chemical entities (NCEs) based on pharmacokinetic behavior plays a major role in modern drug discovery. Despite advancement of drug delivery methods, the oral route remains the most frequent route of administration for approved new drugs. Therefore, during lead optimization it is essential to identify NCEs with sufficient oral absorption predicted using a variety of in vitro and in vivo assays. It is well recognized that in order for a NCE to achieve reasonable oral absorption, it will need to have adequate aqueous solubility, as well as intestinal permeability [1], Recent advancements in chemistry, such as parallel and combinatorial synthesis, have resulted in a multifold increase in the number of compounds that are available for evaluation in new drug discovery. Furthermore, a variety of improved structural chemistry... 

Pizzi RA. The science and politics of stem cells, Modern Drug Discovery 5 32-37... 

Source Vogelson CT. Advances in drug delivery systems, Modern Drug Discovery 4(April) 49-50, 52 (2001). 

Source Willis RC. Nature s pharma sea, Modern Drug Discovery 5 32-38 (2002). 

Stahl, M., Cuba, W. and Kansy, M. (2006) Integrating molecular design resources within modern drug discovery research the Roche experience. Drug Discovery Today, 11, 326-333. 

Chemoinformatics refers to the systems and scientific methods used to store, retrieve, and analyze the immense amount of molecular data that are generated in modern drug-discovery efforts. In general, these data fall into one of four categories structural, numerical, annotation/text, and graphical. However, it is fair to say that the molecular structure data are the most unique aspect that differentiate chemoinformatics from other database applications (1). Molecular structure refers to the 1-, 2-, or 3-D representations of molecules. Examples of numerical data include biological activity, p/C, log/5, or analytical results, to name a few. Annotation includes information such as experimental notes that are associated with a structure or data point. Finally, any structure... 

Ganesan, A. (2008) The impact of natural products upon modern drug discovery. Current Opinion in Chemical Biology, 12, 306-317. 

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