Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening

Patrick Markt; Rasmus K Petersen; Esben N Flindt; Karsten Kristiansen; Johannes Kirchmair; Gudrun Spitzer; Simona Distinto; Daniela Schuster; Gerhard Wolber; Christian Laggner; Thierry Langer

doi:10.1021/jm800128k

Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening

Patrick Markt, Rasmus K Petersen, Esben N Flindt, Karsten Kristiansen, Johannes Kirchmair, Gudrun Spitzer, Simona Distinto, Daniela Schuster, Gerhard Wolber, Christian Laggner, Thierry Langer

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

Peroxisome proliferator-activated receptors (PPARs) are important targets for drugs used in the treatment of atherosclerosis, dyslipidaemia, obesity, type 2 diabetes, and other diseases caused by abnormal regulation of the glucose and lipid metabolism. We applied a virtual screening workflow based on a combination of pharmacophore modeling with 3D shape and electrostatic similarity screening techniques to discover novel scaffolds for PPAR ligands. From the resulting 10 virtual screening hits, five tested positive in human PPAR ligand-binding domain (hPPAR-LBD) transactivation assays and showed affinities for PPAR in a competitive binding assay. Compounds 5, 7, and 8 were identified as PPAR-alpha agonists, whereas compounds 2 and 9 showed agonistic activity for hPPAR-gamma. Moreover, compound 9 was identified as a PPAR-delta antagonist. These results demonstrate that our virtual screening protocol is able to enrich novel scaffolds for PPAR ligands that could be useful for drug development in the area of atherosclerosis, dyslipidaemia, and type 2 diabetes.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	51
Issue number	20
Pages (from-to)	6303-6317
Number of pages	14
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm800128k
Publication status	Published - 23. Oct 2008

Keywords

Cell Line, Tumor
Chemistry, Physical
Combinatorial Chemistry Techniques
Drug Evaluation, Preclinical
Humans
Imaging, Three-Dimensional
Ligands
Models, Molecular
Peroxisome Proliferator-Activated Receptors
Physicochemical Phenomena
Protein Structure, Tertiary
Static Electricity
Structure-Activity Relationship
Transcriptional Activation

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10.1021/jm800128k

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Markt, P., Petersen, R. K., Flindt, E. N., Kristiansen, K., Kirchmair, J., Spitzer, G., Distinto, S., Schuster, D., Wolber, G., Laggner, C., & Langer, T. (2008). Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening. Journal of Medicinal Chemistry, 51(20), 6303-6317. https://doi.org/10.1021/jm800128k

@article{484bb1a0ee1f11dd84b0000ea68e967b,

title = "Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening",

abstract = "Peroxisome proliferator-activated receptors (PPARs) are important targets for drugs used in the treatment of atherosclerosis, dyslipidaemia, obesity, type 2 diabetes, and other diseases caused by abnormal regulation of the glucose and lipid metabolism. We applied a virtual screening workflow based on a combination of pharmacophore modeling with 3D shape and electrostatic similarity screening techniques to discover novel scaffolds for PPAR ligands. From the resulting 10 virtual screening hits, five tested positive in human PPAR ligand-binding domain (hPPAR-LBD) transactivation assays and showed affinities for PPAR in a competitive binding assay. Compounds 5, 7, and 8 were identified as PPAR-alpha agonists, whereas compounds 2 and 9 showed agonistic activity for hPPAR-gamma. Moreover, compound 9 was identified as a PPAR-delta antagonist. These results demonstrate that our virtual screening protocol is able to enrich novel scaffolds for PPAR ligands that could be useful for drug development in the area of atherosclerosis, dyslipidaemia, and type 2 diabetes.",

keywords = "Cell Line, Tumor, Chemistry, Physical, Combinatorial Chemistry Techniques, Drug Evaluation, Preclinical, Humans, Imaging, Three-Dimensional, Ligands, Models, Molecular, Peroxisome Proliferator-Activated Receptors, Physicochemical Phenomena, Protein Structure, Tertiary, Static Electricity, Structure-Activity Relationship, Transcriptional Activation",

author = "Patrick Markt and Petersen, {Rasmus K} and Flindt, {Esben N} and Karsten Kristiansen and Johannes Kirchmair and Gudrun Spitzer and Simona Distinto and Daniela Schuster and Gerhard Wolber and Christian Laggner and Thierry Langer",

year = "2008",

month = oct,

day = "23",

doi = "10.1021/jm800128k",

language = "English",

volume = "51",

pages = "6303--6317",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "20",

}

Markt, P, Petersen, RK, Flindt, EN, Kristiansen, K, Kirchmair, J, Spitzer, G, Distinto, S, Schuster, D, Wolber, G, Laggner, C & Langer, T 2008, 'Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening', Journal of Medicinal Chemistry, vol. 51, no. 20, pp. 6303-6317. https://doi.org/10.1021/jm800128k

Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening. / Markt, Patrick; Petersen, Rasmus K; Flindt, Esben N et al.

In: Journal of Medicinal Chemistry, Vol. 51, No. 20, 23.10.2008, p. 6303-6317.

Research output: Contribution to journal › Journal article › Research › peer-review

TY - JOUR

T1 - Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening

AU - Markt, Patrick

AU - Petersen, Rasmus K

AU - Flindt, Esben N

AU - Kristiansen, Karsten

AU - Kirchmair, Johannes

AU - Spitzer, Gudrun

AU - Distinto, Simona

AU - Schuster, Daniela

AU - Wolber, Gerhard

AU - Laggner, Christian

AU - Langer, Thierry

PY - 2008/10/23

Y1 - 2008/10/23

N2 - Peroxisome proliferator-activated receptors (PPARs) are important targets for drugs used in the treatment of atherosclerosis, dyslipidaemia, obesity, type 2 diabetes, and other diseases caused by abnormal regulation of the glucose and lipid metabolism. We applied a virtual screening workflow based on a combination of pharmacophore modeling with 3D shape and electrostatic similarity screening techniques to discover novel scaffolds for PPAR ligands. From the resulting 10 virtual screening hits, five tested positive in human PPAR ligand-binding domain (hPPAR-LBD) transactivation assays and showed affinities for PPAR in a competitive binding assay. Compounds 5, 7, and 8 were identified as PPAR-alpha agonists, whereas compounds 2 and 9 showed agonistic activity for hPPAR-gamma. Moreover, compound 9 was identified as a PPAR-delta antagonist. These results demonstrate that our virtual screening protocol is able to enrich novel scaffolds for PPAR ligands that could be useful for drug development in the area of atherosclerosis, dyslipidaemia, and type 2 diabetes.

AB - Peroxisome proliferator-activated receptors (PPARs) are important targets for drugs used in the treatment of atherosclerosis, dyslipidaemia, obesity, type 2 diabetes, and other diseases caused by abnormal regulation of the glucose and lipid metabolism. We applied a virtual screening workflow based on a combination of pharmacophore modeling with 3D shape and electrostatic similarity screening techniques to discover novel scaffolds for PPAR ligands. From the resulting 10 virtual screening hits, five tested positive in human PPAR ligand-binding domain (hPPAR-LBD) transactivation assays and showed affinities for PPAR in a competitive binding assay. Compounds 5, 7, and 8 were identified as PPAR-alpha agonists, whereas compounds 2 and 9 showed agonistic activity for hPPAR-gamma. Moreover, compound 9 was identified as a PPAR-delta antagonist. These results demonstrate that our virtual screening protocol is able to enrich novel scaffolds for PPAR ligands that could be useful for drug development in the area of atherosclerosis, dyslipidaemia, and type 2 diabetes.

KW - Cell Line, Tumor

KW - Chemistry, Physical

KW - Combinatorial Chemistry Techniques

KW - Drug Evaluation, Preclinical

KW - Humans

KW - Imaging, Three-Dimensional

KW - Ligands

KW - Models, Molecular

KW - Peroxisome Proliferator-Activated Receptors

KW - Physicochemical Phenomena

KW - Protein Structure, Tertiary

KW - Static Electricity

KW - Structure-Activity Relationship

KW - Transcriptional Activation

U2 - 10.1021/jm800128k

DO - 10.1021/jm800128k

M3 - Journal article

C2 - 18821746

VL - 51

SP - 6303

EP - 6317

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 20

ER -

Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening

Abstract

Keywords

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