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J Med Chem. 2013 Feb 14;56(3):1197-210. doi: 10.1021/jm301653f. Epub 2013 Jan 29.

Systematic exploration of dual-acting modulators from a combined medicinal chemistry and biology perspective.

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Discovery Sciences, Computational Biology, AstraZeneca R&D , Alderley Park, Macclesfield, Cheshire, SK10 4TG, U.K.


The traditional drug discovery strategy of pursuing "one compound-one target" has had difficulties delivering novel therapies for complex diseases currently lacking adequate treatments. An alternative and complementary approach is the design of multitargeted modulators simultaneously addressing multiple pathological mechanisms or overcoming pathway robustness. In this study, we propose a methodology to increase the probability of success for developing dual-acting modulators by systematically and rationally evaluating all dual-acting modulator opportunities within a specific disease area. This approach employs a combination of a five-step medicinal chemistry evaluation and a two-step biological analysis to help select the optimal target combination. It provides a novel methodology suitable for widespread application across disease areas. To exemplify the power of this approach, we focus on an analysis of the gastrointestinal (GI) disease area to identify opportunities supported by current literature data.

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