1. Αποθετήριο Παραδοτέων Υποτρόφων Δράσεων ΕΣΠΑ Τριτοβάθμιας Εκπαίδευσης 2017-2023
2. Όλο το Αποθετήριο
3. Ερευνητικές ομάδες

Τύπος:	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Discovery of selective inhibitor leads by targeting an allosteric site in insulin-regulated aminopeptidase
Συγγραφέας:	[EL] Τεμπονέρας, Γιάννης[EN] Temponeras, Ioannis [EL] Χηνιάδης, Λυκούργος[EN] Chiniadis, Lykourgos [EL] Παπακυριακού, Αθανάσιος[EN] Papakyriakou, Athanasios [EL] Στρατίκος, Ευστράτιος[EN] Stratikos, Efstratios
Ημερομηνία:	18/06/2021
Περίληψη:	Insulin-Regulated aminopeptidase (IRAP) is a zinc-dependent aminopeptidase with several important biological functions and is an emerging pharmaceutical target for cognitive enhancement and immune system regulation. Aiming to discover lead-like IRAP inhibitors with enhanced selectivity versus homologous enzymes, we targeted an allosteric site at the C-terminal domain pocket of IRAP. We compiled a library of 2.5 million commercially available compounds from the ZINC database, and performed molecular docking at the target pocket of IRAP and the corresponding pocket of the homologous endoplasmic reticulum aminopeptidase 1 (ERAP1). Of the top compounds that showed high selectivity, 305 were further analyzed by molecular dynamics simulations and free energy calculations, leading to the election of 33 compounds for in vitro evaluation. Two orthogonal functional assays were employed: one using a small fluorogenic substrate and one following the degradation of oxytocin, a natural peptidic substrate of IRAP. In vitro evaluation suggested that several of the compounds tested can inhibit IRAP, but the inhibition profile was dependent on substrate size, consistent with the allosteric nature of the targeted site. Overall, our results describe several novel leads as IRAP inhibitors and suggest that the C-terminal domain pocket of IRAP is a promising target for developing highly selective IRAP inhibitors.
Γλώσσα:	Αγγλικά
Σελίδες:	14
DOI:	10.3390/ph14060584
EISSN:	1424-8247
Θεματική κατηγορία:	[EL] Φαρμακευτική χημεία[EN] Medicinal chemistry
Λέξεις-κλειδιά:	aminopeptidase; lead-like inhibitors; immune system; peptides; docking; molecular dynamics; free-energy calculations; enzymatic assays; allosteric; cognitive enhancement
Κάτοχος πνευματικών δικαιωμάτων:	© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Όροι και προϋποθέσεις δικαιωμάτων:	This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
Ηλεκτρονική διεύθυνση του τεκμηρίου στον εκδότη:	https://www.mdpi.com/1424-8247/14/6/584
Ηλεκτρονική διεύθυνση περιοδικού:	https://www.mdpi.com/journal/pharmaceuticals
Τίτλος πηγής δημοσίευσης:	Pharmaceuticals
Τεύχος:	6
Τόμος:	14
Σελίδες τεκμηρίου (στην πηγή):	Article no 584
Σημειώσεις:	This research is co-financed by Greece and the European Union (European Social FundESF) through the Operational Programme «Human Resources Development, Education and Lifelong Learning 2014-2020» in the context of the project “Structure-based discovery of modulatory molecules for the action of aminopeptidase IRAP” (MIS: 5047831).
Εμφανίζεται στις συλλογές:	Ερευνητικές ομάδες