Discovery of α,β‐ and α,γ‐Diamino Acid Scaffolds for the Inhibition of M1 Family Aminopeptidases

Gumpena, R.; Kishor, Chandan; Ganji, Roopa Jones; Addlagatta, A.

doi:10.1002/cmdc.201100298

Cited by 14 publications

(10 citation statements)

References 31 publications

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“…1 A , confirmed by molecular modelling for unsubstituted analogue 1a (Fig. S1), and interactions displayed by certain disubstituted ligands, including diaminocarboxylic compounds complexed with Escherichia coli APN [39]. …”

Section: Resultsmentioning

confidence: 82%

A structural insight into the P1 S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases

Węglarz-Tomczak

Berlicki

Pawełczak

et al. 2016

European Journal of Medicinal Chemistry

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N'-substituted 1,2-diaminoethylphosphonic acids and 1,2-diaminoethylphosphinic dipeptides were explored to unveil the structural context of the unexpected selectivity of these inhibitors of M1 alanine aminopeptidases (APNs) versus M17 leucine aminopeptidase (LAP). The diaminophosphonic acids were obtained via aziridines in an improved synthetic procedure that was further expanded for the phosphinic pseudodipeptide system. The inhibitory activity, measured for three M1 and one M17 metalloaminopeptidases of different sources (bacterial, human and porcine), revealed several potent compounds (e.g., Ki = 65 nM of 1u for HsAPN). Two structures of an M1 representative (APN from Neisseria meningitidis) in complex with N-benzyl-1,2-diaminoethylphosphonic acid and N-cyclohexyl-1,2-diaminoethylphosphonic acid were determined by the X-ray crystallography. The analysis of these structures and the models of the phosphonic acid complexes of the human ortholog provided an insight into the role of the additional amino group and the hydrophobic substituents of the ligands within the S1 active site region.

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Section: Resultsmentioning

confidence: 82%

A structural insight into the P1 S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases

Węglarz-Tomczak

Berlicki

Pawełczak

et al. 2016

European Journal of Medicinal Chemistry

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“…Structures of the inhibitor-enzyme complexes were modeled using the crystal structure of native Nm APN [13] as the starting point and the complex of P. falciparum APN with inhibitor 4 as the template [30]. Although several crystal structures of bacterial ( E. coli ) aminopeptidase N were recently published [35–39], the protozoan enzyme seemed to be better suited for our modeling studies. First, it is the only representative of the APNs that has been structurally characterized in the complex with the studied hPheP(CH 2 )Phe inhibitor.…”

Section: Resultsmentioning

confidence: 99%

“…Potential P1-S1 interactions may include electrostatic and ionic binding of 2,3- and 2,4-disubstituted ligands (similarly to e.g. bestatine [35] and diamino compounds [39,40]) in the glutamate-rich anionic site formed by Glu117, Glu260 and Glu316. Furthermore, a set of characteristic amide side chains is located in the S1 periphery.…”

Section: Resultsmentioning

confidence: 99%

An integrated approach to the ligand binding specificity of Neisseria meningitidis M1 alanine aminopeptidase by fluorogenic substrate profiling, inhibitory studies and molecular modeling

et al. 2013

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Neisseria meningitides is a gram-negative diplococcus bacterium and is the main causative agent of meningitis and other meningococcal diseases. Alanine aminopeptidase from N. meningitides (NmAPN) belongs to the family of metallo-exopeptidase enzymes, which catalyze the removal of amino acids from the N-terminus of peptides and proteins, and are found among all the kingdoms of life. NmAPN is suggested to be mostly responsible for proteolysis and nutrition delivery, similar to the orthologs from other bacteria. To explore the possibility of NmAPN being a potential drug target for inhibition and development of novel therapeutic agents, the specificity of the S1 and S1′ binding sites were explored using an integrated approach. Initially, an extensive library consisting of almost 100 fluorogenic substrates derived from both natural and unnatural amino acids, were used to obtain a detailed substrate fingerprint of the S1 pocket of NmAPN. A broad substrate tolerance of NmAPN was revealed, with bulky basic and hydrophobic ligands being the most favored substrates. Additionally, the potency of a set of organophosphorus inhibitors of neutral aminopeptidases, amino acid and dipeptide analogues was determined. Inhibition constants in the nanomolar range, determined for phosphinic dipeptides, proves the positive increase in inhibition impact of the P1′ ligand elongation. The results were further verified via molecular modeling and docking of canonical aminopeptidase phosphinic dipeptide inhibitors in the NmAPN active site. These studies present comprehensive characterization of interactions responsible for specific ligand binding. This knowledge provides invaluable insight into understanding of the enzyme and development of novel NmAPN inhibitors.

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“…ACE (Masuyer, Schwager, Sturrock, Isaac, & Acharya, 2012), aminopeptidase (Yang, Liu, Lin, & Li, 2013), and termolysin (Gumpena, Kishor, Ganji, & Addlagatta, 2011) are part of the same clan (CL0126) but they are grouped into two different families (PF01401 and PF01433).…”

Section: Convergent Structural Evolution Of Zn Hydrolasesmentioning

confidence: 99%

Efficient Calculation of Enzyme Reaction Free Energy Profiles Using a Hybrid Differential Relaxation Algorithm

Romero¹,

Martin²,

Ramírez³

et al. 2015

Combined Quantum Mechanical and Molecular Mechanical Modelling of Biomolecular Interactions

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Discovery of α,β‐ and α,γ‐Diamino Acid Scaffolds for the Inhibition of M1 Family Aminopeptidases

Cited by 14 publications

References 31 publications

A structural insight into the P1 S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases

A structural insight into the P1 S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases

An integrated approach to the ligand binding specificity of Neisseria meningitidis M1 alanine aminopeptidase by fluorogenic substrate profiling, inhibitory studies and molecular modeling

Efficient Calculation of Enzyme Reaction Free Energy Profiles Using a Hybrid Differential Relaxation Algorithm

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