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Defining Substrate Specificities for Lipase and Phospholipase Candidates

Defining Substrate Specificities for Lipase and Phospholipase Candidates

Published on: November 23, 2016

Testing the substrate-envelope hypothesis with designed pairs of compounds.

Yang Shen¹, Michael D Altman, Akbar Ali

¹Department of Biological Engineering, ‡Department of Chemistry, and ○Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.

ACS Chemical Biology

|August 20, 2013

Summary

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Designing enzyme inhibitors that avoid resistance mutations is key for effective disease treatment. A substrate-envelope strategy limits mutations, creating robust inhibitors for drug-resistant variants.

Area of Science:

Biochemistry
Drug Discovery
Computational Chemistry

Background:

Acquired resistance to therapeutic agents, often from target mutations, impedes effective disease treatment.
Evolutionary dynamics on clinical timescales necessitate novel drug design strategies.
Previous work introduced a computational inverse design method for enzyme targets using a substrate-envelope constraint.

Purpose of the Study:

To experimentally validate the substrate-envelope hypothesis for designing inhibitors resistant to mutations.
To investigate the impact of inhibitor size relative to the substrate envelope on drug resistance.
To compare the binding affinity of envelope-respecting versus envelope-violating inhibitors against drug-resistant variants.

Main Methods:

Computational inverse design of enzyme inhibitors with and without the substrate-envelope constraint.

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Synthesis of novel inhibitor derivatives.

Biochemical assays to measure binding affinity to wild-type and drug-resistant enzyme variants.

Main Results:

Envelope-respecting inhibitors maintained robust binding across a panel of drug-resistant variants.
Envelope-violating inhibitors showed reduced affinity to at least one resistant variant compared to wild-type.
Pairs of similar inhibitors, differing only in substrate envelope adherence, demonstrated distinct resistance profiles.

Conclusions:

The substrate-envelope hypothesis provides a viable strategy to design inhibitors that minimize susceptibility to resistance mutations.
Adhering to the substrate envelope is crucial for developing broadly effective therapeutic agents against mutating targets.
This approach has significant implications for the development of next-generation therapeutics for diseases driven by rapid evolution.