Scaffold target-based

Foloppe, N., Chen, I.J., Davis, B., Hold, A., Morley, D., Howes, R. A structure-based strategy to identify new molecular scaffolds targeting the bacterial ribosomal A-site. Bioorg. Med. Chem. 

Rosania GR, Lee JW, Ding L, Yoon HS, Chang YT (2003) Combinatorial approach to organelle-targeted fluorescent library based on the styryl scaffold. J Am Chem Soc 125 1130-1131... 

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). 

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