We developed an unbiased forward genetic screening approach that uncovers the molecular on- and off-target space of drug candidates at unprecedented amino acid resolution. We use chemical mutagenesis combined with next generation sequencing and advanced bioinformatics algorithms to identify specific amino acid sites that are critical for the drug’s mode of action. Through saturating screens we are able to map the compound-target binding interface.
The Acus screening approach interrogates the complete genome in an entirely unbiased fashion. The technology identifies target structures and no prior knowledge on a potential mechanism of action is needed. It can also function as an orthogonal validation tool for existing data. Importantly, our approach includes the analysis of essential genes, that are frequently targeted by small molecules, and that are largely invisible to other screening technologies.
Through saturated screening, the Acus technology allows to map compound-target binding interfaces at amino acid resolution. The screen thus not only identifies the relevant target, but also the amino acids required for the interaction with the drug compound. The information obtained from this “structural biology by genetics” approach is a key for advanced and rational drug design and drug modifications.
The Acus screening approach requires no compound modifications but can use any relevant active substance. Importantly, the screen is performed in intact cellular systems, reflecting physiological conditions that ensure physiologically meaningful results. Finally, our technology can be applied to a wide range of different cellular systems enabling compound and indication-specific screening setups.