Design of Small Molecules

Changes induced by SNPs (or other mutations) in the protein targets of drugs may result in the medicine being ineffective. In this case, the relevant disease may remain untreated, or else an expensive drug discovery effort will have to be undertaken to identify new molecules that are able to affect the mutant protein. Given that most current small molecule discovery strategies rely on expensive 

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Most commonly used FRET pairs for the design of small molecule FRET... 

Kikuchi, K. (2004). Recent advances in the design of small molecule-based FRET sensors for cell biology. Trends Anal. Chem. 23, 407-415. 

The overexpression of GSTs in some cancer cells, particularly of GST Pl-1, offers an opportunity to detect and treat some cancer types (e.g., ovarian cancer). Recent developments in the design of small molecules that either inhibit the catalytic activity of GST Pl-1 or use GST Pl-1 catalytic site to release the actual anticancer agent, have shown promising results in preclinical studies, with the graduation of 66 and 96 as potential anticancer drug candidates currently undergoing clinical trials. 

Galactose oxidase exhibits a surprisingly low specificity for the primary alcohol but is completely regioselective secondary alcohols are not substrates. This re-gioselectivity suggests potential synthetic applications (117) and has raised interest in the design of small molecule catalysts mimicking GO reactivity. 

DXMS-guided Design of Small Molecules that Target Protein-Protein Interaction Surfaces 391... 

Andersson, P. M., Linusson, A., Wold, S., Sjostrom, M., Lundstedt, T., and Norden, B. (1999) Design of small molecule libraries for lead exploration. In Molecular diversity in drug design, Dean, P. M. and Lewis, R. A. (eds.), Kluwer Academic Publishers, pp. 197-220. 

Application of molecular recognition principles allows the design of small molecules able to interact with biological systems for use, e.g. as anticancer drugs. 

Hay, D.L. and Smith, D.M., Adrenomedullin receptors molecular identity and function. Peptides 22, 1753-1763, 2001 Julian, M., Cacho, M., Garcia, M.A. et al., Adrenomedullin a new target for the design of small molecule modulators with promising pharmacological activities, Eur. J. Med. Chem. 40,737-750,2005 Shimosawa, T. and Fujita, T., AdrenomeduUin and its related peptides, Endocr. J. 52,1-10, 2005 Zudaire, E., Portal-Nunez, S., and Cuttitta, F., The central role of adrenomedullin in host defense, J. Leak. Biol. 80, 237-244, 2006 Hamid, S.A. and Baxter, G.F, A critical cytoprotec-tive role of endogenous adrenomedullin in acute myocardial infarction, J. Mol. Cell Cardiol. 41, 360-363, 2006. 

Despite the extensive amount of work that has been done toward understanding the molecular recognition process, the design of small molecules that exhibit potency to biological receptors remains a challenge. Most efforts to date have been driven by... 

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