Identification of novel microsomal prostaglandin E2synthase-1 (mPGES-1) lead inhibitors from Fragment Virtual Screening.
Identification of new microsomal prostaglandin E2synthase-1 (mPGES-1) inhibitors is currently sought for the treatment of cancer and inflammation. Here we show the results of a Fragment Virtual Screening campaign using the X-ray crystal structure of human mPGES-1 (PDB code: 4AL0). Among the fragments selected and biologically tested, 6 (9H-indeno [1,2-b] [1,2,5]oxadiazolo [3,4-e]pyrazin-9-one) showed the most promising mPGES-1 inhibitory activity (∼30% inhibition at 10 μM). A minimal structure-based optimization of 6 led to compounds 15, 20 and 21, with a promising enhancement of the inhibitory activity (IC50= 4.6 ± 0.2 μM for 15; IC50= 2.4 ± 1.0 μM for 20; IC50= 2.4 ± 0.8 μM for 21). The unprecedented chemical core and the possibility of synthesizing novel derivatives reveal a new and attractive field of action for the development of mPGES-1 inhibitors with potential anti-inflammatory and anticancer properties.
Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano, Italy.
Gianluigi
G
Lauro
Department of Science, University of Basilicata, Viale dell'Ateneo Lucano 10, 85100 Potenza, Italy.
Michele
M
Manfra
Department of Chemical Sciences, University of Napoli Federico II, Via Cintia 4, I-80126 Napoli, Italy.
Silvana
S
Pedatella
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany.
Katrin
K
Fischer
Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano, Italy; Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany.
Vincenza
V
Cantone
Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano, Italy.
Stefania
S
Terracciano
Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano, Italy.
Alessia
A
Bertamino
Department of Pharmacy, Università degli Studi di Napoli "Federico II", Via Montesano 49, 80131 Napoli, Italy.
Carmine
C
Ostacolo
Department of Pharmacy, Università degli Studi di Napoli "Federico II", Via Montesano 49, 80131 Napoli, Italy.
Isabel
I
Gomez-Monterrey
Department of Science, University of Basilicata, Viale dell'Ateneo Lucano 10, 85100 Potenza, Italy.
Mauro
M
De Nisco
Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano, Italy.
Raffaele
R
Riccio
Department of Pharmacy, Università degli Studi di Napoli "Federico II", Via Montesano 49, 80131 Napoli, Italy.
Ettore
E
Novellino
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany.
Oliver
O
Werz
Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano, Italy. Electronic address: pcampiglia@unisa.it.
Pietro
P
Campiglia
Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano, Italy. Electronic address: bifulco@unisa.it.
Giuseppe
G
Bifulco
D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D000071876:Prostaglandin-E Synthases / Q000037:antagonists & inhibitors*; D014584:User-Computer Interface
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases
Cancer; Inflammation; Molecular docking; Virtual screening; mPGES-1 inhibitors