2. Academic Validation
  3. The Dynamic Nonprime Binding of Sampatrilat to the C-Domain of Angiotensin-Converting Enzyme

The Dynamic Nonprime Binding of Sampatrilat to the C-Domain of Angiotensin-Converting Enzyme

  • J Chem Inf Model. 2016 Dec 27;56(12):2486-2494. doi: 10.1021/acs.jcim.6b00524.
Rajni K Sharma 1,  Marlene Espinoza-Moraga 1,  Horacio Poblete 2,  Ross G Douglas 3 4,  Edward D Sturrock 3 4,  Julio Caballero 2,  Kelly Chibale 1 5 6
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
  • 2 Centro de Bioinformática y Simulación Molecular, Facultad de Ingeniería, Universidad de Talca , 2 Norte 685, Casilla 721, Talca, Chile.
  • 3 Institute of Infectious Disease and Molecular Medicine and Department of Integrative Biomedical Sciences, University of Cape Town , Observatory 7935, South Africa.
  • 4 Department of Integrative Biomedical Sciences, University of Cape Town , Observatory 7925, South Africa.
  • 5 Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Rondebosch 7701, South Africa.
  • 6 South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town , Rondebosch 7701, South Africa.
PMID: 27959521 DOI: 10.1021/acs.jcim.6b00524
Abstract

Sampatrilat is a vasopeptidase inhibitor that inhibits both angiotensin I-converting Enzyme (ACE) and neutral endopeptidase. ACE is a zinc dipeptidyl Carboxypeptidase that contains two extracellular domains (nACE and cACE). In this study the molecular basis for the selectivity of sampatrilat for nACE and cACE was investigated. Enzyme inhibition assays were performed to evaluate the in vitro ACE domain selectivity of sampatrilat. The inhibition of the C-domain (Ki = 13.8 nM) by sampatrilat was 12.4-fold more potent than that for the N-domain (171.9 nM), indicating differences in affinities for the respective ACE domain binding sites. Interestingly, replacement of the P2 group of sampatrilat with an aspartate abrogated its C-selectivity and lowered the potency of the inhibitor to activities in the micromolar range. The molecular basis for this selective profile was evaluated using molecular modeling methods. We found that the C-domain selectivity of sampatrilat is due to occupation of the lysine side chain in the S1 and S2 subsites and interactions with Glu748 and Glu1008, respectively. This study provides new insights into ligand interactions with the nonprime binding site that can be exploited for the design of domain-selective ACE inhibitors.

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