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.

Manuscript Highlights

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Strategies for Substrate Envelope-Guided Design to Avoid Drug Resistance

Stay within the substrate envelope: avoid contacts with protease residues (red bar) beyond those of the natural substrate(s). Extend beyond the substrate envelope only if contacting invariant conserved residues such as the catalytic side chains (green bar), or toward the solvent. Exploit untapped regions of the substrate envelope to further increase potency. Add macrocycles to preposition the inhibitor in a binding-competent state, making sure the macrocycle itself obeys the rules above.

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