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

Sharma, Rajni; Espinoza-Moraga, Marlene; Poblete, Horacio; Douglas, Ross G.; Sturrock, Edward D.; Caballero, Julio; Chibale, Kelly

doi:10.1021/acs.jcim.6b00524

Cited by 12 publications

(30 citation statements)

References 42 publications

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“…A previous study compared the affinity and selectivity of sampatrilat and samAsp for cACE and nACE 18. This reported that sampatrilat inhibited both cACE and nACE in the low nanomolar range, but it was 12.4‐fold more selective for cACE ( K i of 13.8 and 171.9 n m respectively).…”

Section: Resultsmentioning

confidence: 98%

“…However, the molecular dynamics study predicted movement away from the docked poses, which is inconsistent with the crystal structures. This is probably because there are important water‐/ion‐mediated interactions in the crystal structures, which are not accounted for in the molecular modelling study 18.…”

Section: Resultsmentioning

confidence: 99%

“…The study measuring the affinity of sampatrilat/samAsp for cACE and nACE also included molecular modelling studies (docking and molecular dynamics) [18]. The docking studies predicted two potential orientations of sampatrilat in both domains, with the inhibitor lysine side chain located in either the S 1 or S 2 subsites.…”

Section: Comparison With Sampatrilat/samasp Molecular Modelling Resultsmentioning

confidence: 99%

“…In a detailed kinetic study, Sharma et al . 18 evaluated the in vitro ACE domain selectivity of sampatrilat. They observed that the inhibition of cACE ( K i = 13.8 n m ) by sampatrilat was 12.4‐fold more potent than that for the nACE ( K i = 171.9 n m ), indicating differences in affinities for the respective ACE domain‐binding sites (Table 1).…”

Section: Introductionmentioning

confidence: 99%

“…It is a hydrophilic inhibitor that contains one weakly acidic phenolic (tyrosine) group), two more strongly acidic carboxylate (tyrosine carboxylate and the central carboxylate) groups, and one strongly basic primary amine (lysine) group. In a detailed kinetic study, Sharma et al [18] evaluated the in vitro ACE domain selectivity of sampatrilat. They observed that the inhibition of cACE (K i = 13.8 nM) by sampatrilat was 12.4-fold more potent than that for the nACE (K i = 171.9 nM), indicating differences in affinities for the respective ACE domain-binding sites ( Table 1).…”

Section: Introductionmentioning

confidence: 99%

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Crystal structures of sampatrilat and sampatrilat‐Asp in complex with human ACE – a molecular basis for domain selectivity

et al. 2018

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Angiotensin‐1‐converting enzyme (ACE) is a zinc metallopeptidase that consists of two homologous catalytic domains (known as nACE and cACE) with different substrate specificities. Based on kinetic studies it was previously reported that sampatrilat, a tight‐binding inhibitor of ACE, K i = 13.8 nm and 171.9 nm for cACE and nACE respectively [Sharma et al., Journal of Chemical Information and Modeling (2016), 56, 2486–2494], was 12.4‐fold more selective for cACE. In addition, samAsp, in which an aspartate group replaces the sampatrilat lysine, was found to be a nonspecific and lower micromolar affinity inhibitor. Here, we report a detailed three‐dimensional structural analysis of sampatrilat and samAsp binding to ACE using high‐resolution crystal structures elucidated by X‐ray crystallography, which provides a molecular basis for differences in inhibitor affinity and selectivity for nACE and cACE. The structures show that the specificity of sampatrilat can be explained by increased hydrophobic interactions and a H‐bond from Glu403 of cACE with the lysine side chain of sampatrilat that are not observed in nACE. In addition, the structures clearly show a significantly greater number of hydrophilic and hydrophobic interactions with sampatrilat compared to samAsp in both cACE and nACE consistent with the difference in affinities. Our findings provide new experimental insights into ligand binding at the active site pockets that are important for the design of highly specific domain selective inhibitors of ACE.DatabaseThe atomic coordinates and structure factors for N‐ and C‐domains of ACE bound to sampatrilat and sampatrilat‐Asp complexes (6F9V, 6F9R, 6F9T and 6F9U respectively) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Comparison With Sampatrilat/samasp Molecular Modelling Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Crystal structures of sampatrilat and sampatrilat‐Asp in complex with human ACE – a molecular basis for domain selectivity

et al. 2018

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Evaluating the benefits of renin-angiotensin system inhibitors as cancer treatments

Perini

Dmello

Nero

et al. 2020

Pharmacology & Therapeutics

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Molecular Basis for Omapatrilat and Sampatrilat Binding to Neprilysin—Implications for Dual Inhibitor Design with Angiotensin-Converting Enzyme

et al. 2020

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Neprilysin (NEP) and angiotensin-converting enzyme (ACE) are two key zinc-dependent metallopeptidases in the natriuretic peptide and kinin systems and renin−angiotensin− aldosterone system, respectively. They play an important role in blood pressure regulation and reducing the risk of heart failure. Vasopeptidase inhibitors omapatrilat and sampatrilat possess dual activity against these enzymes by blocking the ACE-dependent conversion of angiotensin I to the potent vasoconstrictor angiotensin II while simultaneously halting the NEP-dependent degradation of vasodilator atrial natriuretic peptide. Here, we report crystal structures of omapatrilat, sampatrilat, and sampatrilat-ASP (a sampatrilat analogue) in complex with NEP at 1.75, 2.65, and 2.6 Å, respectively. A detailed analysis of these structures and the corresponding structures of ACE with these inhibitors has provided the molecular basis of dual inhibitor recognition involving the catalytic site in both enzymes. This new information will be very useful in the design of safer and more selective vasopeptidase inhibitors of NEP and ACE for effective treatment in hypertension and heart failure.

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

Cited by 12 publications

References 42 publications

Crystal structures of sampatrilat and sampatrilat‐Asp in complex with human ACE – a molecular basis for domain selectivity

Crystal structures of sampatrilat and sampatrilat‐Asp in complex with human ACE – a molecular basis for domain selectivity

Evaluating the benefits of renin-angiotensin system inhibitors as cancer treatments

Molecular Basis for Omapatrilat and Sampatrilat Binding to Neprilysin—Implications for Dual Inhibitor Design with Angiotensin-Converting Enzyme

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