Arginine Analogues Incorporating Carboxylate Bioisosteric Functions are Micromolar Inhibitors of Human Recombinant DDAH-1

Sara Tommasi; Chiara Zanato; Benjamin C. Lewis; Pramod C. Nair; Sergio Dall'Angelo; Matteo Zanda; Arduino A. Mangoni

doi:10.1039/C5OB01843A

Arginine Analogues Incorporating Carboxylate Bioisosteric Functions are Micromolar Inhibitors of Human Recombinant DDAH-1

Sara Tommasi, Chiara Zanato, Benjamin C. Lewis, Pramod C. Nair, Sergio Dall'Angelo, Matteo Zanda, Arduino A. Mangoni

Medical Sciences

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

Abstract

Dimethylarginine dimethylaminohydrolase (DDAH) is a key enzyme involved in the metabolism of asymmetric dimethylarginine (ADMA) and N-monomethyl arginine (NMMA), which are endogenous inhibitors of the nitric oxide synthase (NOS) family of enzymes. Two isoforms of DDAH have been identified in humans, DDAH-1 and DDAH-2. DDAH-1 inhibition represents a promising strategy to limit the overproduction of NO in pathological states without affecting the homeostatic role of this important messenger molecule. Here we describe the design and synthesis of 12 novel DDAH-1 inhibitors and report their derived kinetic parameters, IC50 and Ki. Arginine analogue 10a, characterized by an acylsulfonamide isosteric replacement of the carboxylate, showed a 13-fold greater inhibitory potential relative to the known DDAH-1 inhibitor, L-257. Compound 10a was utilized to study the putative binding interactions of human DDAH-1 inhibition using molecular dynamics simulations. The latter suggests that several stabilizing interactions occur in the DDAH-1 active-site, providing structural insights for the enhanced inhibitory potential demonstrated by in vitro inhibition studies.

Original language	English
Pages (from-to)	11315-11330
Number of pages	16
Journal	Organic & Biomolecular Chemistry
Volume	46
Issue number	13
Early online date	23 Sept 2015
DOIs	https://doi.org/10.1039/C5OB01843A
Publication status	Published - 14 Dec 2015

Bibliographical note

Acknowledgements
The authors thank eResearch SA for computational time and
data storage facility. PCN acknowledges Flinders University for
Research Fellowship. The authors would also like to thank Prof. John O. Miners for his helpful suggestions and the opportunity to use the facilities at the Department of Clinical Pharmacology at Flinders University, Dr Andrew Rowland for his help in the development of the hDDAH-1 activity assay and Rhys Murphy for his help in conducting the polarimetry experiments. We thank Prof. James Leiper (MRC Clinical Sciences Centre, London, UK) for a sample of L-257.
We thank also the EPSRC National Mass Spectrometry Service Centre (Swansea, UK), for performing HRMS analyses.

Keywords

DDAH-1
Arginine analogues
Carboxylate bioisostetric functions

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10.1039/C5OB01843ALicence: Unspecified

Sergio Dall'Angelo
Person: Academic Related - Research

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title = "Arginine Analogues Incorporating Carboxylate Bioisosteric Functions are Micromolar Inhibitors of Human Recombinant DDAH-1",

abstract = "Dimethylarginine dimethylaminohydrolase (DDAH) is a key enzyme involved in the metabolism of asymmetric dimethylarginine (ADMA) and N-monomethyl arginine (NMMA), which are endogenous inhibitors of the nitric oxide synthase (NOS) family of enzymes. Two isoforms of DDAH have been identified in humans, DDAH-1 and DDAH-2. DDAH-1 inhibition represents a promising strategy to limit the overproduction of NO in pathological states without affecting the homeostatic role of this important messenger molecule. Here we describe the design and synthesis of 12 novel DDAH-1 inhibitors and report their derived kinetic parameters, IC50 and Ki. Arginine analogue 10a, characterized by an acylsulfonamide isosteric replacement of the carboxylate, showed a 13-fold greater inhibitory potential relative to the known DDAH-1 inhibitor, L-257. Compound 10a was utilized to study the putative binding interactions of human DDAH-1 inhibition using molecular dynamics simulations. The latter suggests that several stabilizing interactions occur in the DDAH-1 active-site, providing structural insights for the enhanced inhibitory potential demonstrated by in vitro inhibition studies.",

keywords = "DDAH-1, Arginine analogues, Carboxylate bioisostetric functions",

author = "Sara Tommasi and Chiara Zanato and Lewis, {Benjamin C.} and Nair, {Pramod C.} and Sergio Dall'Angelo and Matteo Zanda and Mangoni, {Arduino A.}",

note = "Acknowledgements The authors thank eResearch SA for computational time and data storage facility. PCN acknowledges Flinders University for Research Fellowship. The authors would also like to thank Prof. John O. Miners for his helpful suggestions and the opportunity to use the facilities at the Department of Clinical Pharmacology at Flinders University, Dr Andrew Rowland for his help in the development of the hDDAH-1 activity assay and Rhys Murphy for his help in conducting the polarimetry experiments. We thank Prof. James Leiper (MRC Clinical Sciences Centre, London, UK) for a sample of L-257. We thank also the EPSRC National Mass Spectrometry Service Centre (Swansea, UK), for performing HRMS analyses.",

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AU - Nair, Pramod C.

AU - Dall'Angelo, Sergio

AU - Zanda, Matteo

AU - Mangoni, Arduino A.

N1 - Acknowledgements The authors thank eResearch SA for computational time and data storage facility. PCN acknowledges Flinders University for Research Fellowship. The authors would also like to thank Prof. John O. Miners for his helpful suggestions and the opportunity to use the facilities at the Department of Clinical Pharmacology at Flinders University, Dr Andrew Rowland for his help in the development of the hDDAH-1 activity assay and Rhys Murphy for his help in conducting the polarimetry experiments. We thank Prof. James Leiper (MRC Clinical Sciences Centre, London, UK) for a sample of L-257. We thank also the EPSRC National Mass Spectrometry Service Centre (Swansea, UK), for performing HRMS analyses.

PY - 2015/12/14

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N2 - Dimethylarginine dimethylaminohydrolase (DDAH) is a key enzyme involved in the metabolism of asymmetric dimethylarginine (ADMA) and N-monomethyl arginine (NMMA), which are endogenous inhibitors of the nitric oxide synthase (NOS) family of enzymes. Two isoforms of DDAH have been identified in humans, DDAH-1 and DDAH-2. DDAH-1 inhibition represents a promising strategy to limit the overproduction of NO in pathological states without affecting the homeostatic role of this important messenger molecule. Here we describe the design and synthesis of 12 novel DDAH-1 inhibitors and report their derived kinetic parameters, IC50 and Ki. Arginine analogue 10a, characterized by an acylsulfonamide isosteric replacement of the carboxylate, showed a 13-fold greater inhibitory potential relative to the known DDAH-1 inhibitor, L-257. Compound 10a was utilized to study the putative binding interactions of human DDAH-1 inhibition using molecular dynamics simulations. The latter suggests that several stabilizing interactions occur in the DDAH-1 active-site, providing structural insights for the enhanced inhibitory potential demonstrated by in vitro inhibition studies.

AB - Dimethylarginine dimethylaminohydrolase (DDAH) is a key enzyme involved in the metabolism of asymmetric dimethylarginine (ADMA) and N-monomethyl arginine (NMMA), which are endogenous inhibitors of the nitric oxide synthase (NOS) family of enzymes. Two isoforms of DDAH have been identified in humans, DDAH-1 and DDAH-2. DDAH-1 inhibition represents a promising strategy to limit the overproduction of NO in pathological states without affecting the homeostatic role of this important messenger molecule. Here we describe the design and synthesis of 12 novel DDAH-1 inhibitors and report their derived kinetic parameters, IC50 and Ki. Arginine analogue 10a, characterized by an acylsulfonamide isosteric replacement of the carboxylate, showed a 13-fold greater inhibitory potential relative to the known DDAH-1 inhibitor, L-257. Compound 10a was utilized to study the putative binding interactions of human DDAH-1 inhibition using molecular dynamics simulations. The latter suggests that several stabilizing interactions occur in the DDAH-1 active-site, providing structural insights for the enhanced inhibitory potential demonstrated by in vitro inhibition studies.

KW - DDAH-1

KW - Arginine analogues

KW - Carboxylate bioisostetric functions

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DO - 10.1039/C5OB01843A

M3 - Article

SN - 1477-0520

VL - 46

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JO - Organic & Biomolecular Chemistry

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IS - 13

ER -

Arginine Analogues Incorporating Carboxylate Bioisosteric Functions are Micromolar Inhibitors of Human Recombinant DDAH-1

Abstract

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Keywords

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Sergio Dall'Angelo

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