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

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.

SUBMITTER: Long MJ

PROVIDER: S-EPMC6698416 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Long Marcus Jc MJ Liu Xuyu X Aye Yimon Y

Current opinion in chemical biology 20190323

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 designe ...[more]

PMID: 30913473

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

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

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