Synthesis and activity of small molecule GPR40 agonists

Garrido, Dulce; Corbett, David F.; Dwornik, Kate A.; Goetz, Aaron S.; Littleton, Thomas R.; McKeown, Steve C.; Mills, Wendy Y.; Smalley, Terrence L.; Briscoe, Celia P.; Peat, Andrew J.

doi:10.1016/j.bmcl.2006.01.007

Cited by 100 publications

(34 citation statements)

References 7 publications

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“…The terminal phenoxy ring is located inside the hydrophobic pocket formed by Leu186 and Asn241. The introduction of the (S,S)-cyclopropyl acid head group of compound 2 led to a significant improvement in potency over the ethyl-linked analogs [10]. The possible reason may be that the compound 2 is more rigid than GW9508, and is losing less torsional free energy compared with GW9508 during docking.…”

Section: Molecular Dockingmentioning

confidence: 97%

“…In the many reported GPR40 agonists [10,11,13,14], parasubstituted phenyl propionic acid scaffold has emerged as a common structure motif, and compounds having an aromatic ring and an acid group have shown good agonistic activity. Both characteristics can be found in CA agonists such as GW9508 and TUG424 (Fig.…”

Section: Molecular Dockingmentioning

confidence: 99%

“…The first two of these combined give the docking energy while the first and third terms build up the binding energy. During all these interactions, the electrostatic interaction between ligands and receptor is the most important, because in most cases it can decide the binding strength and the location of ligand, while the hydrophobic interaction of some certain groups can affect the agonistic activity to a larger extent [10,11]. The energy information is listed in Table 1, and the interaction modes of the agonists and GPR40 are depicted in Fig.…”

Section: Molecular Dockingmentioning

confidence: 99%

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Molecular docking and molecular dynamics simulation studies of GPR40 receptor–agonist interactions

Jiang

et al. 2010

Journal of Molecular Graphics and Modelling

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Section: Molecular Dockingmentioning

confidence: 97%

Section: Molecular Dockingmentioning

confidence: 99%

Section: Molecular Dockingmentioning

confidence: 99%

See 1 more Smart Citation

Molecular docking and molecular dynamics simulation studies of GPR40 receptor–agonist interactions

Jiang

et al. 2010

Journal of Molecular Graphics and Modelling

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“…Briscoe et al [8] reported that 8, 11-eicosatriynoic acid was the most potent fatty acid with respect to GPR40, and reported a EC 50 of lM. A potent, selective, nM-affinity, small molecule GPR40 agonist was reported by Garrido et al [36] and the structure activity relationship (SAR) was explored. Garrido et al [36], also showed that carboxamide derivatives activate GPR40 indicating that the carboxyl group is not an absolute requirement for a GPR40 agonist and receptor activation.…”

Section: Gpr40mentioning

confidence: 99%

“…A potent, selective, nM-affinity, small molecule GPR40 agonist was reported by Garrido et al [36] and the structure activity relationship (SAR) was explored. Garrido et al [36], also showed that carboxamide derivatives activate GPR40 indicating that the carboxyl group is not an absolute requirement for a GPR40 agonist and receptor activation. However, the carboxyl moiety does increase agonistic efficacy more than is observed with the carboxamide replacement analogs.…”

Section: Gpr40mentioning

confidence: 99%

Fatty Acid Binding Receptors and Their Physiological Role in Type 2 Diabetes

Swaminath

2008

Archiv der Pharmazie

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G‐protein‐coupled receptors (GPCRs) respond to various physiological ligands such as photons, ions, and small molecules that include amines, fatty acids, and amino acids to peptides, proteins and steroids. Therefore, this family of proteins represents an attractive target for biopharmaceutical research [1]. The physiological role of fatty acids and other lipid molecules as important signal mediators is well studied in various metabolic pathways [2]. Acute administration of free fatty acids (FFAs) stimulates insulin release. Conversely, chronic exposure to high levels of free fatty acids leads to impairment of β cell function and lipotoxicity. However, the receptors through which these fatty acids and lipids act were unknown, until the identification of fatty acid binding receptors: GPR40, GPR41, GPR43, and GPR119. Based on their tissue‐expression profile, and pharmacologic analysis, the fatty acid binding receptors along with lipid binding receptor GPR119 are linked to diabetes and obesity. They play a critical role in the metabolic regulation of insulin release and glucose homeostasis. In this review, the mechanism of receptor activation, pharmacology, and the physiological functions of the fatty acid binding receptors will be discussed.

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Virtual Screening

Muegge

Oloff

2010

Burger's Medicinal Chemistry and Drug Discovery

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Virtual screening can be considered as in silico analog to high‐throughput screening. It is a knowledge‐driven approach toward finding new lead structures for drug discovery. There are a large variety of different virtual screening approaches and strategies available today. They include ligand‐based approaches such as compound similarity searching, pharmacophore searching, and applying predictive models derived using machine learning techniques as well as structure‐based approaches such as docking and scoring that use information about the protein target structures. Triaging hit sets using target‐independent filters such as drug‐likeness and diversity is an additional component of virtual screening. Using different virtual screening approaches in synergy has become more prevalent. Virtual screening applications have been combined with modern drug discovery technologies such as fragment‐based screening, combinatorial chemistry, and scaffold hopping methods to increase their effectiveness as lead identification tools.

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Synthesis and activity of small molecule GPR40 agonists

Cited by 100 publications

References 7 publications

Molecular docking and molecular dynamics simulation studies of GPR40 receptor–agonist interactions

Molecular docking and molecular dynamics simulation studies of GPR40 receptor–agonist interactions

Fatty Acid Binding Receptors and Their Physiological Role in Type 2 Diabetes

Virtual Screening

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