Chemotypes diversity

The chemotypic diversity of kava within Vanuatu is greater than elsewhere in the Pacific, and variability among the cultivars from Pentecost in Vanuatu is as great as... 

In general, the attempt to retest every compound that passes a statistically defined threshold of activity for each assay and to implement a concomitant assay interference test has been rewarded by recovery of a full spectrum of biological activities and diverse chemotypes in the confirmed hit set. In many cases, the compounds that the medicinal chemists ultimately judge to be the best starting points for lead development exhibited only modest activity (e.g., IC50 values of 0.5-5 pM) in HTS. 

Welker, M. Brunke, M. Preussel, K. Lippert, I. von Dohren, H. Diversity and distribution of microcystis (Cyanobacteria) oligopeptide chemotypes from natural communities studied by single-colony mass spectrometry. Microbiology 2004,150, 1785-1796. 

Not only does the limited diversity of the compound database curtail the choice of lead, the process for assessing screening hits to see if they define a tractable lead is also limited by resources, particularly in those specialist assays that would predict the ability of the chosen lead class to successfully yield an approval in a particular therapeutic field. The process is therefore driven mainly by consideration of activity against the target. Therefore chemotypes with adequate but less than maximal potency for the target but freedom from damaging side activity remain undetected in this process. 

An analysis of more than 130 preclinical candidates that had attrited during further development showed the failure of the chemotype approach (i.e. that a compound of the same/similar chemotype will have similar risks of attrition and that a structurally diverse chemotype will offer the best approach to minimize attrition risk) and 2D structure-based methods to be able to effectively differentiate compounds [29]. Thus, the risk of failing or succeeding in development is not related to being of the same chemotype , and differentiation by this method may not be the most effective way dangers are both that a valuable series/chemotype could be discarded because of one bad result and that a structurally different compound may actually have similar off-target effects (e.g. due to the decoration versus the scaffold). 

Natural products continue to play a dominant role in the discovery of leads for the development of drugs to treat human diseases. Such chemical agents have traditionally also played a major role in drug discovery and still constitute a prolific source of novel chemotypes or pharmacophores for medicinal chemistry. Natural product-based scaffolds find key importance in drug discovery as well as in optimizing chemical diversity... 

In addition to the preceding kinase inhibitors, a number of patents describe compounds that are claimed to be active against PKB (e.g., diamino tri-azines, diaminopyrimidines or 5-aminocarbonylindazoles) [1,144]. Although in general no kinase inhibitory data are provided in these patents, the diverse chemical scaffolds covered in these specifications may represent promising new chemotypes for the future generation of PKB kinase-selective inhibitors. 

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