Medicinal chemist system biology

It is critically important to capture biological assay data and allow the medicinal chemist to access the information for SAR analysis. Many software systems have been developed for this purpose, and we briefly describe two of them below. 

Analysts like to make chemical measurements to the highest quality they can, and this is possible with modem instrumentation and good analytical practice. Chemical parameters are generally measured more accurately and reproducibly than parameters measured in biological systems, and the results are more reliable than values calculated by software from structure alone (e.g., calculated log P, pKa). Of all the information available to medicinal chemists, measured chemical parameters are probably the most reliable. With these thoughts in mind, it makes sense not to... 

Ring systems 63-74 have attracted much attention from medicinal chemists, and examples of biological activities for a large range of new derivatives have been published for several of these systems since 1995. A selection of these is presented below. 

The second reason that bisulfite compounds are useful is that they are soluble in water. Some small (that is, low molecular weight) aldehydes and ketones are water-soluble—acetone is an example. But most larger (more than four or so carbon atoms) aldehydes and ketones are not. This does not usually matter to most chemists as we often want to carry out reactions in organic solvents rather than water. But it can matter to medicinal chemists, who make compounds that need to be compatible with biological systems. And in one case, the solubility of bisulfite adduct in water is literally vital. 

Anatoxin-a is a natnrally occnrring nenrotoxic alkaloid, prodnced by several strains of cyanobacteria. Originally, the species, Anabaena flos aquae, was the sonrce of the toxin, which was conse-qnently named anatoxin-a. Since its isolation (Devlin et al. 1977) and characterisation as a (lA,(5A)-2-acetyl-9-azabicyclo[4.2.1]nonane (Hnber et al. 1972 Koskinen and Rapoport 1985) in the 1970s, anatoxin-a (1 Fig. 7.1 A) has stimnlated the scientific commnnity worldwide. While synthetic chemists devised methods for the constmction of the novel 9-azabicyclo[4.2.1]nonane ring system, medicinal chemists were intrigned by its powerful biological activity. 

ATOM records are used to specify molecules which occur frequently in biological systems. These are called the known molecules and include amino acids, heme, cofactors, some of the unnatural amino acids used by medicinal chemists and a variety of molecules of general interest to GRID users. Here is a Protein Data Bank ATOM record ... 

The reactivity profile established for pentafluoropyridine, where the 4, 2- and 6-positions are sequentially, regiospecifically substituted by a succession of oxygen-centred nucleophiles, has allowed medicinal chemists to use pentafluoropyridine as a core scaffold for the synthesis of small arrays of biologically active pyridine systems that fall within the Lipinski parameters (see Table 11.3). 

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