A Novel Multi-step Virtual Screening for the Identification of Human and Mouse mPGES-1 Inhibitors

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 w...

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Bibliographic Details
Published in:Molecular informatics 2016-09, Vol.35 (8-9), p.358-368
Main Authors: Corso, G., Alisi, M. A., Cazzolla, N., Coletta, I., Furlotti, G., Garofalo, B., Mangano, G., Mancini, F., Vitiello, M., Ombrato, Rosella
Format: Article
Language:English
Subjects:
Animals
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - metabolism
Enzymes
homology modelling
human/mouse species specificity
Humans
Ligands
Mice
Models, Molecular
Molecular Docking Simulation - methods
mPGES-1
Prostaglandin-E Synthases - antagonists & inhibitors
Protein Binding - physiology
Structure-Activity Relationship
virtual screening
workflow development
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Summary: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.
ISSN:1868-1743
1868-1751
DOI:10.1002/minf.201600024