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The Design and Development of a Potent and Selective Novel Diprolyl Derivative that Binds to the N-domain of Angiotensin-I Converting Enzyme

DOI: 10.1021/acs.jmedchem.7b01478 DOI Help

Authors: Stephen Fienberg (University of Cape Town) , Gyles E. Cozier (University of Bath) , K. Ravi Acharya (University of Bath) , Kelly Chibale (University of Cape Town) , Edward D. Sturrock (University of Cape Town)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: December 2017
Diamond Proposal Number(s): 12342

Abstract: Angiotensin-I converting enzyme (ACE) is a Zinc metalloprotease consisting of two catalytic domains (N- and C-). Most clinical ACE inhibitor(s) (ACEi) have been shown to inhibit both domains non-selectively resulting in adverse effects such as cough and angioedema. Selectively inhibiting the individual domains is likely to reduce these effects and potentially treat fibrosis in addition to hypertension. ACEi from GVK Biosciences database were inspected for possible N-domain selective binding patterns. From this set, a diprolyl chemical series was modelled using docking simulations. The series was expanded based on key target interactions involving residues known to impart N-domain selectivity. In total, seven diprolyl compounds were synthesised and tested for N-domain selective ACE inhibition. One compound with an aspartic acid in the P2 position (compound 16) displayed potent inhibition (Ki = 12 nM), and was 84-fold more selective towards the N-domain. A high-resolution crystal structure of compound 16 in complex with the N-domain revealed the molecular basis for the observed selectivity.

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

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