title: Systematic exploration of dual-acting modulators from a combined medicinal chemistry and biology perspective.
abstract: 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.
authors.affiliation: Discovery Sciences, Computational Biology, AstraZeneca R&D , Alderley Park, Macclesfield, Cheshire, SK10 4TG, U.K.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Bornot
authors.forename: Udo
authors.initials: U
authors.lastname: Bauer
authors.forename: Alastair
authors.initials: A
authors.lastname: Brown
authors.forename: Mike
authors.initials: M
authors.lastname: Firth
authors.forename: Caroline
authors.initials: C
authors.lastname: Hellawell
authors.forename: Ola
authors.initials: O
authors.lastname: Engkvist
mesh_terms: D002626:Chemistry, Pharmaceutical; D055808:Drug Discovery; D011949:Receptors, Cholecystokinin / Q000737:chemistry; D018040:Receptors, Neurokinin-1 / Q000737:chemistry; D011957:Receptors, Opioid / Q000737:chemistry
chemical_list: D011949:Receptors, Cholecystokinin; D018040:Receptors, Neurokinin-1; D011957:Receptors, Opioid