Discovery of novel, non-acidic mPGES-1 inhibitors by virtual screening with a multistep protocol

Noha, Stefan M.; Fischer, Katrin; Koeberle, Andreas; Garscha, Ulrike; Werz, Oliver; Schuster, Daniela

doi:10.1016/j.bmc.2015.05.045

Cited by 16 publications

(9 citation statements)

References 55 publications

(72 reference statements)

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“…On the other hand, pharmacophore models with acceptable statistical parameters could be generated when only non‐acid inhibitors (five inhibitors) were employed (Figure a). Similar results were achieved by Noha et al . and Waltenberg et al ,.…”

Section: Resultssupporting

confidence: 91%

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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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Section: Resultssupporting

confidence: 91%

“…This strategy resulted in the acquisition of five bioactive molecules and 13 inactive ones (Figures and S2) in our experimental conditions. The 28% success rate achieved by the pharmacophore model is equivalent to that of Noha and coworkers …”

Section: Discussionsupporting

confidence: 58%

Virtual screening and biological evaluation of novel antipyretic compounds

et al. 2017

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“…LVJ, a benzimidazole‐5‐carboxamide derivative and a very potent mPGES‐1 inhibitor M2 (Figure ) (PDB‐4BPM) also forms a hydrogen bond with His 53 and interacts with Phe44, Leu39 and Gln36 . Noha et al, (2015) identified two non‐acidic mPGES‐1 inhibitors (Figure ), a methoxy benzohydrazide M3 (IC50=4.5 μM) and a benzamide M4 (IC50=3.8 μM), from a database of 1.3 million compounds which made important contacts with F44 and L39 . Thus the POC3 binding pocket of mPGES‐1 consists of residues which play an important role in the binding of non‐acidic mPGES‐1 inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“…Thus the POC3 binding pocket of mPGES‐1 consists of residues which play an important role in the binding of non‐acidic mPGES‐1 inhibitors. This is a promising finding since the acidic mPGES‐1 inhibitors have several drawbacks including toxicity, loss of efficiency in vivo and non‐selectivity . These have been attributed to toxic metabolites formed by amide hydrolysis and cross‐reactivity with cyclooxygenase (COX) enzymes ,.…”

Section: Resultsmentioning

confidence: 99%

Ligand‐based Modeling for the Prediction of Pharmacophore Features for Multi‐targeted Inhibition of the Arachidonic Acid Cascade

Devi

Rajasekar

Ghorai

et al. 2017

Molecular Informatics

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The single-target drugs against the arachidonic acid inflammatory pathway are associated with serious side effects, hence, as a first step towards multi-target drugs, we have studied the pharmacophoric features common to the inhibitors of 5-lipoxygenase-activating protein (FLAP), microsomal prostaglandin E-synthase 1 (mPGES-1) and leukotriene A4 hydrolase (LTA4H). FLAP and mPGES-1 shared subfamily-specific positions (SSPs) and four mPGES-1 inhibitors binding to them mapped onto the pharmacophore derived from FLAP inhibitors (Ph-FLAP). The reactions of mPGES-1 and LTA4H had high structural similarity. The pharmacophore derived from two substrate mimic inhibitors of LTA4H (Ph-LTA4H) also mapped onto three mPGES-1 inhibitors. Screening of in-house database for Ph-FLAP and Ph-LTA4H identified one compound, C1. It inhibited the production of the mPGES-1 product, prostaglandin E2 (PGE2) by 97.8±1.6 % at 50 μM in HeLa cells and can be a starting point for designing molecules inhibiting all three targets simultaneously.

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“…All these aspects make mPGES‐1 a well‐known drug target for inflammation with reduced risk of undesired side effects if compared to classical NSAIDs and COXIBs . Since 1999, when the enzyme was first discovered, great efforts have been made in the development of efficient ways to silence its activity, leading to the identification of potent sub‐micromolar inhibitors of human mPGES‐1, as extensively reviewed,, However, since most inhibitors of the human enzyme are inactive on its murine ortholog, determining species‐specificity, the clinical translation is difficult.…”

Section: Introductionmentioning

confidence: 99%

A Novel Multi‐step Virtual Screening for the Identification ofHumanandMousemPGES‐1 Inhibitors

Corso

Alisi

Cazzolla

et al. 2016

Molecular Informatics

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We present here the development of a novel virtual screening protocol combining Structure-based and Ligand-based drug design approaches for the identification of mouse mPGES-1 inhibitors. We used the existing 3D structural data of the murine enzyme to hypothesize the inhibitors binding mode, which was the starting point for docking simulations, shape screening, and pharmacophore hypothesis screening. The protocol allowed the identification of 16 mouse mPGES-1 inhibitors with low micromolar activity, which, notably, also inhibit the human enzyme in the same concentration range. The inhibitors predicted binding mode is expected to be the base for the rational drug design of new potent dual species inhibitors of human and murine mPGES-1.

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Discovery of novel, non-acidic mPGES-1 inhibitors by virtual screening with a multistep protocol

Abstract: Graphical abstract

Cited by 16 publications

References 55 publications

Virtual screening and biological evaluation of novel antipyretic compounds

Virtual screening and biological evaluation of novel antipyretic compounds

Ligand‐based Modeling for the Prediction of Pharmacophore Features for Multi‐targeted Inhibition of the Arachidonic Acid Cascade

A Novel Multi‐step Virtual Screening for the Identification ofHumanandMousemPGES‐1 Inhibitors

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