The relative binding affinities to human aldose reductase (ALR2) of three new 7-hydroxy-2-benzyl-4H-1-benzopyran-4-one inhibitors were predicted by free energy perturbation (FEP) simulations. Molecular substitutions were specifically designed to investigate the role of hydrogen bonding at the active site of ALR2. Starting from the lead inhibitor 7-hydroxy-2-(4'-hydroxy-benzyl)-4H-1-benzopyran-4-one, the 4'-hydroxyl was mutated to methyl and to trifluoromethyl, and an hydroxyl at position 8 was additionally introduced. Once synthesized and tested as inhibitors of ALR2, the compounds displayed variations of K-i that were in qualitative to quantitative agreement with the calculated relative free energies of binding. The results, discussed in terms of balance between free energies of solvation and free energies of binding to ALR2, elucidate the importance of hydrogen bonding with Thr113 and with Trp111 and cofactor, and provide a rationale to the observed differences in binding affinities. (C) 2002 Elsevier Science Ltd. All rights reserved.

Binding of 1-benzopyran-4-one derivatives to aldose reductase: A free energy perturbation study / Rastelli, Giulio; Costantino, Luca; Gamberini, Maria Cristina; A., Del Corso; U., Mura; Jm, Petrash; Am, Ferrari; S., Pacchioni. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - STAMPA. - 10:(2002), pp. 1427-1436. [10.1016/S0968-0896(01)00408-4]

Binding of 1-benzopyran-4-one derivatives to aldose reductase: A free energy perturbation study

RASTELLI, Giulio;COSTANTINO, Luca;GAMBERINI, Maria Cristina;
2002

Abstract

The relative binding affinities to human aldose reductase (ALR2) of three new 7-hydroxy-2-benzyl-4H-1-benzopyran-4-one inhibitors were predicted by free energy perturbation (FEP) simulations. Molecular substitutions were specifically designed to investigate the role of hydrogen bonding at the active site of ALR2. Starting from the lead inhibitor 7-hydroxy-2-(4'-hydroxy-benzyl)-4H-1-benzopyran-4-one, the 4'-hydroxyl was mutated to methyl and to trifluoromethyl, and an hydroxyl at position 8 was additionally introduced. Once synthesized and tested as inhibitors of ALR2, the compounds displayed variations of K-i that were in qualitative to quantitative agreement with the calculated relative free energies of binding. The results, discussed in terms of balance between free energies of solvation and free energies of binding to ALR2, elucidate the importance of hydrogen bonding with Thr113 and with Trp111 and cofactor, and provide a rationale to the observed differences in binding affinities. (C) 2002 Elsevier Science Ltd. All rights reserved.
10
1427
1436
Binding of 1-benzopyran-4-one derivatives to aldose reductase: A free energy perturbation study / Rastelli, Giulio; Costantino, Luca; Gamberini, Maria Cristina; A., Del Corso; U., Mura; Jm, Petrash; Am, Ferrari; S., Pacchioni. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - STAMPA. - 10:(2002), pp. 1427-1436. [10.1016/S0968-0896(01)00408-4]
Rastelli, Giulio; Costantino, Luca; Gamberini, Maria Cristina; A., Del Corso; U., Mura; Jm, Petrash; Am, Ferrari; S., Pacchioni
File in questo prodotto:
File Dimensione Formato  
Binding-benzopyran-FEP-Rastelli-BMC2002.pdf

non disponibili

Tipologia: Versione dell'editore (versione pubblicata)
Dimensione 310.79 kB
Formato Adobe PDF
310.79 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/308007
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 10
  • ???jsp.display-item.citation.isi??? 11
social impact