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

Research output: Contribution to journalArticle

7 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 languageEnglish
Pages (from-to)11315-11330
Number of pages16
JournalOrganic & Biomolecular Chemistry
Volume46
Issue number13
Early online date23 Sep 2015
DOIs
Publication statusPublished - 14 Dec 2015

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inhibitors
carboxylates
Arginine
analogs
enzymes
metabolism
nitric oxide
interactions
molecular dynamics
kinetics
synthesis
dimethylargininase
molecules
simulation
Enzymes
Molecular Dynamics Simulation
Kinetic parameters
Metabolism
Nitric Oxide Synthase
Inhibitory Concentration 50

Keywords

  • DDAH-1
  • Arginine analogues
  • Carboxylate bioisostetric functions

Cite this

Arginine Analogues Incorporating Carboxylate Bioisosteric Functions are Micromolar Inhibitors of Human Recombinant DDAH-1. / Tommasi, Sara; Zanato, Chiara; Lewis, Benjamin C.; Nair, Pramod C.; Dall'Angelo, Sergio; Zanda, Matteo; Mangoni, Arduino A.

In: Organic & Biomolecular Chemistry, Vol. 46, No. 13, 14.12.2015, p. 11315-11330.

Research output: Contribution to journalArticle

Tommasi, Sara ; Zanato, Chiara ; Lewis, Benjamin C. ; Nair, Pramod C. ; Dall'Angelo, Sergio ; Zanda, Matteo ; Mangoni, Arduino A. / Arginine Analogues Incorporating Carboxylate Bioisosteric Functions are Micromolar Inhibitors of Human Recombinant DDAH-1. In: Organic & Biomolecular Chemistry. 2015 ; Vol. 46, No. 13. pp. 11315-11330.
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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.",
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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.

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