Decoding IRAP Selectivity: Quantum Simulations Reveal Mechanism Behind Enzyme Inhibition

Kuano are excited to announce the publication of the results from our collaboration with the Mulholland group at the University of Bristol modelling the reaction mechanism of IRAP*, a promising drug target in a range of diseases including breast cancer, neurodegenerative diseases, cardiac fibrosis and diabetes. Insights generated by this project have been used to design low micromolar macrocycle inhibitors with the potential to be developed as therapeutic agents.

IRAP is an enzyme involved in several biological processes, including the degradation of peptide hormones, glucose metabolism and insulin sensitivity regulation. Its role is to cleave hormone peptides, including vasopressin, oxytocin, and angiotensin III. However, very similar peptides, such as angiotensin IV, act as cognitive enhancers by inhibiting IRAP activity. IRAP is known to bind similarly to all of these potential substrates and until now it has been an unresolved puzzle why the enzyme selectively metabolizes oxytocin but not angiotensin IV.

Our research used molecular and quantum simulations to understand this selectivity at a molecular level. We discovered that the active site’s interactions, particularly with the catalytic Zinc ion, differ in the two systems, leading to varying stability of reaction intermediates. Kuano has leveraged these structural insights from our simulations to guide AI-driven drug design — not only for IRAP, but across a broad range of challenging therapeutic targets. Our platform integrates quantum mechanics with AI to identify and exploit mechanistic determinants of enzyme function, enabling the rational design of next-generation inhibitors.

M. Hanževački, R.M. Twidale, E.J.M. Lang, W. Gerrard, D.W. Wright, V. Stojevic,  A.J. Mulholland, “Quantum Mechanics/Molecular Mechanics Simulations Distinguish Insulin-Regulated Aminopeptidase Substrate (Oxytocin) and Inhibitor (AngiotensinIV) and Reveal Determinants of Activity and Inhibition”, Journal of Chemical Information and Modeling, DOI: 10.1021/acs.jcim.5c00869

*IRAP (Insulin-regulated aminopeptidase) is also known as LNPEP (Leucyl-cystinyl Aminopeptidase)