This talk will focus on over a decade of drug discovery efforts and medicinal chemistry research focused on developing allosteric ligands to modulate kinases, GPCRs and phospholipases and highlight tool compounds and clinical candidates. Without question, targeting allosteric sites provides unique mechanisms for target modulation as well as unprecedented levels of selectivity.  I will discuss the benefits, issues and challenges with the allosteric approach for target modulation, with particular attention placed on class A, B and C GPCRs. Issues concerning 'molecular switches', subtle structural modifications that modulate either the mode of pharmacology of family subtype selectivity, will be discussed as well as the need to identify scaffold that possess 'molecular locks'.   Related to this concept, the need to fully evaluate metabolites of allosteric ligands is critical, and I will highlight examples where metabolites have proven both detrimental and beneficial by virtue of 'molecular switches' derived from oxidative metabolism.  I will also address the concept of allosteric agonism and highlight the issues governing this approach; moreover, data will be presented that supports targeting positive allosteric modulation over allosteric agonism is a variety of contexts.  Finally, I will showcase a number of examples where allosteric approaches have provided highly selective tools that enabled the dissection of the contributions of discrete receptors to the efficacy of pan-orthosteric ligands for a number of CNS disorders including schizophrenia, Parkinson's disease and Alzheimer's disease.

Adventures in allosteric drug discovery

246th National Meeting (2013)

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