Genie in a bottle: controlled release helps tame natural polypharmacology?

Genie in a bottle: controlled release helps tame natural polypharmacology? Curr Opin Chem Biol. 2019 Mar 22;51:48-56 Authors: Long MJ, Liu X, Aye Y Abstract Ability to faithfully report drug-target interactions constitutes a major critical parameter in preclinical/clinical settings. Yet the assessment of target engagement remains challenging, particularly for promiscuous and/or polypharmacologic ligands. Drawing from our improved insights into native electrophile signaling and emerging technologies that profile and interrogate these non-enzyme-assisted signaling subsystems, we posit that 'trained' polypharmocologic covalent inhibitors can be designed. Accumulating evidence indicates that electrophile-modified states at fractional occupancy can alter cell fate. Thus, by understanding sensing preferences and ligandable regions favored by the natural electrophilic signals at individual protein-ligand resolution, we can better evaluate target engagement and develop a function-guided understanding of polypharmacology. PMID: 30913473 [PubMed - as supplied by publisher]
Source: Current Opinion in Chemical Biology - Category: Biochemistry Authors: Tags: Curr Opin Chem Biol Source Type: research