The recently crystallized structure of microsomal prostaglandin E2 synthase 1 (mPGES-1) in complex with the inhibitor LVJ (PDB code: 4BPM) offered new structural information for the optimization of the previously identified lead compound 1 (IC50 = 4.16 ± 0.47 μM), which contains the privileged dihydropyrimidin-2-one chemical core. Systematic optimization of 1, through accurate structure-based design, provided compound 4 with a 10-fold improved mPGES-1 inhibitory activity (IC50 = 0.41 ± 0.02 μM). Here we highlight the optimal scaffold decoration pattern of 4 and propose a three-dimensional model for the interaction with this complex trimeric membrane protein. The reported computational insights, together with the accessible one-pot synthetic procedure, stimulate for the generation of further potent dihydropyrimidine-based mPGES-1 inhibitors.

Structural Insights for the Optimization of Dihydropyrimidin-2(1H)-one Based mPGES-1 Inhibitors

TERRACCIANO, Stefania;LAURO, GIANLUIGI;STROCCHIA, MARIA;RICCIO, Raffaele;BRUNO, Ines;BIFULCO, Giuseppe
2015

Abstract

The recently crystallized structure of microsomal prostaglandin E2 synthase 1 (mPGES-1) in complex with the inhibitor LVJ (PDB code: 4BPM) offered new structural information for the optimization of the previously identified lead compound 1 (IC50 = 4.16 ± 0.47 μM), which contains the privileged dihydropyrimidin-2-one chemical core. Systematic optimization of 1, through accurate structure-based design, provided compound 4 with a 10-fold improved mPGES-1 inhibitory activity (IC50 = 0.41 ± 0.02 μM). Here we highlight the optimal scaffold decoration pattern of 4 and propose a three-dimensional model for the interaction with this complex trimeric membrane protein. The reported computational insights, together with the accessible one-pot synthetic procedure, stimulate for the generation of further potent dihydropyrimidine-based mPGES-1 inhibitors.
File in questo prodotto:
File Dimensione Formato  
2015_acs_medchemletters_diidropirimidine_mpges1.pdf

non disponibili

Descrizione: diidropirimidine mpges1
Tipologia: Documento in Post-print (versione successiva alla peer review e accettata per la pubblicazione)
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 2.95 MB
Formato Adobe PDF
2.95 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/4650406
Citazioni
  • ???jsp.display-item.citation.pmc??? 12
  • Scopus 47
  • ???jsp.display-item.citation.isi??? 47
social impact