Long MJ Liu X Aye Y 2019 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. https://sonar.ch/global/documents/97020 eng info:eu-repo/semantics/altIdentifier/doi/10.1016/j.cbpa.2019.02.014 info:eu-repo/semantics/altIdentifier/pmid/30913473 Current opinion in chemical biology. - 2019 Biological Products Delayed-Action Preparations Humans Ligands Polypharmacology Protein Binding Signal Transduction Genie in a bottle: controlled release helps tame natural polypharmacology? http://purl.org/coar/resource_type/c_6501