Inhibitor Design

Avoiding Resistance in Drug Design: Substrate Envelope Guided Design

Drug design typically focuses on a single target of interest, which may inadvertently facilitate the emergence of drug resistance. Instead of considering resistance only after a drug fails, we need a paradigm shift to incorporate preemptive strategies into drug design to avoid resistance.

We combine structure based drug design with organic synthesis and enzymatic assays to design, synthesize and test novel inhibitors to our targets.

The inhibitors, when designed to fit within the substrate envelope, are less likely to elicit drug-resistance mutations.

We demonstrated the success of this strategy with HIV-1 and HCV viral proteases and extend the strategy to other drug targets. This strategy is applicable beyond viral proteases, as multiple or diverse substrates are not necessarily required to define a substrate envelope. Even for an enzyme with a single substrate, the key is to define substrate-enzyme interactions essential for biological function and avoid contacts beyond those of the substrate in inhibitor design.

Relevant Publications

Improving Viral Protease Inhibitors to Counter Drug Resistance.
Kurt Yilmaz N, Swanstrom R, Schiffer CA.
Trends Microbiol. 2016 Jul;24(7):547-557. doi: 10.1016/j.tim.2016.03.010. Epub 2016 Apr 15. Review.