Identification of novel microsomal prostaglandin E2 synthase-1 (mPGES-1) lead inhibitors from Fragment Virtual Screening

Lauro, Gianluigi; Manfra, Michele; Pedatella, Silvana; Fischer, Katrin; Cantone, Vincenza; Terracciano, Stefania; Bertamino, Alessia; Ostacolo, Carmine; Gómez-Monterrey, Isabel; Nisco, Mauro De; Riccio, Raffaele; Novellino, Ettore; Werz, Oliver; Campiglia, Pietro; Bifulco, Giuseppe

doi:10.1016/j.ejmech.2016.09.042

Cited by 18 publications

(15 citation statements)

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“…The combined modulation of both enzymes represents a valuable strategy to intervene with inflammatory pathologies in view of a higher efficacy and safety. In the frame of our ongoing efforts to develop new attractive anti‐inflammatory agents targeting mPGES‐1, we took advantage from the high‐resolution X‐ray structures of human mPGES‐1 in complex with new and potent inhibitors recently published (e. g. PDB code: 4BPM, 4YL1, 5BQH, and 5BQI) …”

Section: Introductionmentioning

confidence: 99%

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A Combinatorial Virtual Screening Approach Driving the Synthesis of 2,4‐Thiazolidinedione‐Based Molecules as New Dual mPGES‐1/5‐LO Inhibitors

et al. 2020

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Dual inhibition of microsomal prostaglandin E2 synthase‐1 (mPGES‐1) and 5‐lipoxygenase (5‐LO), two key enzymes involved in pro‐inflammatory eicosanoid biosynthesis, represents a new strategy for treating inflammatory disorders. Herein we report the discovery of 2,4‐thiazolidinedione‐based mPGES‐1/5‐LO dual inhibitors following a multidisciplinary protocol, involving virtual combinatorial screening, chemical synthesis, and validation of the biological activities for the selected compounds. Following the multicomponent‐based chemical route for the decoration of the 2,4‐thiazolidinedione core, a large library of virtual compounds was built (∼2.0×104 items) and submitted to virtual screening. Nine selected molecules were synthesized and biologically evaluated, disclosing among them four compounds able to reduce the activity of both enzymes in the mid‐ and low‐ micromolar range of activities. These results are of interest for further expanding the chemical diversity around the 2,4‐thiazolidinedione central core, facilitating the identification of novel anti‐inflammatory agents endowed with a promising and safer pharmacological profile.

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Section: Introductionmentioning

confidence: 99%

“…In our research group, the careful analysis of these structural information has been extensively employed for the identification of several new chemotypes featuring mPGES‐1 inhibitory activity …”

Section: Introductionmentioning

confidence: 99%

A Combinatorial Virtual Screening Approach Driving the Synthesis of 2,4‐Thiazolidinedione‐Based Molecules as New Dual mPGES‐1/5‐LO Inhibitors

et al. 2020

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“…To further investigate the pharmacological‐mechanism differences between early and late onset bioactive compounds, only the most potent compounds of each class were considered.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, several recent studies have considered the prostaglandin E 2 synthases (PGES, namely mPGES‐1, mPGES‐2, and cPGES) valuable targets to develop new antipyretic, anti‐inflammatory or anticancer agents . This hypothesis is further supported by the fact that intravenous injection of lipopolysaccharide (LPS), produced by Gram‐negative bacteria (exogenous pyrogen), increases COX‐2 and mPGES‐1 expression in the POA/AH, whereas COX‐2 and mPGES‐1 knockout mice have shown none or reduced febrile response when challenged with LPS or peripheral endotoxin .…”

Section: Introductionmentioning

confidence: 99%

Virtual screening and biological evaluation of novel antipyretic compounds

et al. 2017

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Due to the absence of safety of the antipyretics to patients with cardiovascular dysfunction, new targets to treat inflammation have been pursued. mPGES-1 is a promising target because its inhibition would not cause the side-effects related to COX inhibition. To identify novel inhibitors of mPGES-1, we developed a ligand-based pharmacophore model that differentiates true inhibitors from decoys and enlightens the structure-activity relationships for known mPGES-1 inhibitors. The model (four hydrophobic centers, two hydrogen bond acceptor and two hydrogen bond donor points) was employed to select lead-like compounds from ZINC database for in vivo evaluation. Among the 18 compounds selected, five inhibited the fever induced by LPS. The most potent compound (5-(4-fluorophenyl)-3-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-2,3dihydro-1,3,4-oxadiazol-2-one) is active peripherally (i.v.) or centrally (i.c.v.) (82.18% and 112% reduction, respectively) and reduces (69.13%) hypothalamic PGE production, without significant COX-1/2 inhibition. In conclusion, our in silico approach leads to the selection of a compound that presents the chemical features to inhibit mPGES-1 and reduces fever induced by LPS. Furthermore, the in vivo and in vitro results support the hypothesis that its mechanism of action does not depend on COX inhibition. Hence, it can be considered a promising lead compound for antipyretic development, once it would not have the side-effects of COX-1/2 inhibitors.

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“…The article published by Lauro et al ( 2017 ) presented the possibility to apply hem-diols instead of α-diketones. The condensation of amine 250 with the selected 2,2-dihydroxy-1 H -indene-1,3(2 H )-diones 260 gave compounds 261 in moderate yields (Figure 20 ).…”

Section: Main Partmentioning

confidence: 99%