Target vulnerability is defined as the fraction of the target that is required to be occupied to elicit a desired pharmacodynamic response. Low vulnerability targets must remain continuously occupied at high levels, whereas a high vulnerability target require low levels of occupancy. Cell-wash out experiments (PAE) can provide insight into target vulnerability informing on the consequences of target engagement, once the drug has been removed from the system.

On a high vulnerable target, long residence time(t_R=1/k_off) inhibtor , would mean sustained effects even after drug removal, contributing to the widening of the therapeutic window. In antibacterial space post-antibiotic effect (PAE) provide inference on the interpaly between target vulnerability and kinetic selectivity. However, a fast "turn-over" of the target within the lifetime of the interaction would alleviate the impact of prolonged inhibition once the drug is removed.

My contribution is to understand the effect of target turn-over in modulating the co-relation between residence time and PAE. Furthermore, in assessing how this affects target vulnerability. To this end, we have used techniques like mass spectrometry and chase experiments to determine turn-over, spin-column assay to probe kinetics of our inhibitors, wash-out PAE experiments to assess target vulnerability in Escherichia coli LpxC.

Rajeswari Basu

Appearances