title: Structural Insights for the Optimization of Dihydropyrimidin-2(1H)-one Based mPGES-1 Inhibitors.
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.
authors.affiliation: Department of Pharmacy, University of Salerno , via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Terracciano
authors.affiliation: Department of Pharmacy, University of Salerno , via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Lauro
authors.affiliation: Department of Pharmacy, University of Salerno , via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Strocchia
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Jena , Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Jena , Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Department of Pharmacy, University of Salerno , via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Riccio
authors.affiliation: Department of Pharmacy, University of Salerno , via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Bruno
authors.affiliation: Department of Pharmacy, University of Salerno , via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
keywords: Biginelli reaction; Molecular docking; inflammation; mPGES-1 inhibitors