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001-es BibID:BIBFORM063962
Első szerző:Borics Attila
Cím:The Effect of Pro2 Modifications on the Structural and Pharmacological Properties of Endomorphin-2 / Attila Borics, Jayapal R. Mallareddy, István Timári, Katalin E. Kövér, Attila Keresztes, Géza Tóth
Dátum:2012
ISSN:0022-2623 1520-4804
Megjegyzések:Endomorphins (EM-1 and EM-2) are selective, high affinity agonists of the ?-opioid (MOP) receptor, an important target in pain regulation. Their clinical use is impeded by their poor metabolic stability and limited entry to the central nervous system. In this study the Pro2 residue of EM-2 was modified systematically through substitution by hydroxyproline (Hyp), (S)-?-homoproline (?Pro), 2-aminocyclopentene-1-carboxylic acid (?Acpc) or 2-aminocyclohexene-1-carboxylic acid (?Achc) to obtain stable MOP active compounds. Both Hyp2 and ?Pro2 substitution decreased receptor affinity. Analogues incorporating alicyclic ?-amino acids exhibited diverse receptor binding properties, depending on the configuration of the substituent side-chain. (1S,2R)?Acpc2-EM-2 was shown to have MOP affinity and selectivity comparable to those of EM-2 and proved to act as agonist, while being resistant to proteolysis. NMR and molecular dynamics (MD) studies revealed that bent backbone structures are predominant in the most potent analogues, while their presence is less pronounced in ligands of lower receptor affinity.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
Peptide
Endomorphin-2
opioid receptor
NMR spectroscopy
molecular dynamics (MD) simulations
Megjelenés:Journal Of Medicinal Chemistry. - 55 : 19 (2012), p. 8418-8428. -
További szerzők:Mallareddy, Jayapal Reddy Timári István (1989-) (vegyész) Kövér Katalin, E. (1956-) (vegyész) Keresztes Attila Tóth Géza
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2.

001-es BibID:BIBFORM096569
035-os BibID:113649
Első szerző:Kiss Mariann (vegyész)
Cím:Nanomolar inhibition of human OGA by 2-acetamido-2-deoxy-d-glucono-1,5-lactone semicarbazone derivatives / Mariann Kiss, Erna Szabó, Boglárka Bocska, Luu Thanh Sinh, Conceicao Piedade Fernandes, István Timári, Joseph M. Hayes, László Somsák, Teréz Barna
Dátum:2021
ISSN:0223-5234
Megjegyzések:O-GlcNAcylation is a dynamic post-translational modification mediated by O-linked beta-N-acetylglucosamine transferase (OGT) and O-GlcNAc hydrolase (OGA), that adds or removes a single beta-N-acetylglucosamine (GlcNAc) moiety to or from serine/threonine residues of nucleocytosolic and mitochondrial proteins, respectively. The perturbed homeostasis of O-GlcNAc cycling results in several pathological conditions. Human OGA is a promising therapeutic target in diseases where aberrantly low levels of O-GlcNAc are experienced, such as tauopathy in Alzheimer's disease. A new class of potent OGA inhibitors, 2-acetamido-2-deoxy-D-glucono-1,5-lactone (thio)semicarbazones, have been identified. Eight inhibitors were designed and synthesized in five steps starting from d-glucosamine and with 15-55% overall yields. A heterologous OGA expression protocol with strain selection and isolation has been optimized that resulted in stable, active and full length human OGA (hOGA) isomorph. Thermal denaturation kinetics of hOGA revealed environmental factors affecting hOGA stability. From kinetics experiments, the synthesized compounds proved to be efficient competitive inhibitors of hOGA with K-i-s in the range of similar to 30-250 nM and moderate selectivity with respect to lysosomal beta-hexosaminidases. In silico studies consisting of Prime protein-ligand refinements, QM/MM optimizations and QM/MM-PBSA binding free energy calculations revealed the factors governing the observed potencies, and led to design of the most potent analogue 2-acetamido-2-deoxy-D-glucono-1,5-lactone 4-(2-naphthyl)-semicarbazone 6g (K-i = 36 nM). The protocol employed has applications in future structure based inhibitor design targeting OGA. (C) 2021 The Authors. Published by Elsevier Masson SAS.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
hOGA
Expression
Inhibitor
Glyconolactone semicarbazone
QM/MM-PBSA
Halogen
HalogenHydrogen bond donor
Megjelenés:European Journal of Medicinal Chemistry. - 223 (2021), p. 1-14. -
További szerzők:Szabó Erna (1990-) (Biológus) Bocska Boglárka Sinh, Luu Thanh Fernandes, Conceicao Piedade Timári István (1989-) (vegyész) Hayes, Joseph M. Somsák László (1954-) (vegyész) Barna Teréz (1963-) (vegyész)
Pályázati támogatás:K 109450
OTKA
NKFIH FK125067
Egyéb
NKFIH PD 135034
Egyéb
GINOP-2.3.2-15-2016-00008
GINOP
GINOP-2.3.3-15-2016-00004
GINOP
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