Structure-based, multi-targeted drug discovery approach to eicosanoid inhibition: Dual inhibitors of mPGES-1 and 5-lipoxygenase activating protein (FLAP)

Ho, Joseph; Lee, Matthew R.; Rauch, Charles T.; Aznavour, Kristen; Park, Jonathan S.; Luz, J.G.; Antonysamy, Stephen; Condon, Bradley; Maletic, Milan; Zhang, Aiping; Hickey, Michael J.; Hughes, Norman E.; Chandrasekhar, Srinivasan; Sloan, Ashley V.; Gooding, Karen M.; Yu, Xiaopeng; Kahl, Steven D.; Norman, Bryan H.

doi:10.1016/j.bbagen.2020.129800

Cited by 12 publications

(17 citation statements)

References 40 publications

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“…A new crystal structure of FLAP, bound to a dual microsomal prostaglandin E synthase and FLAP inhibitor (PDB code 6VGC 28 ) was recently published and used to analyse the compounds binding interaction patterns. To evaluate the docking workflow on the structure, redocking and cross-docking experiments 29 were conducted and two key interaction points with the binding site were identified: (i) an ionic (or hydrogen bond) interaction with Lys116 was found to be crucial for FLAP inhibition and (ii) interactions with Phe114 or the co-crystallised water molecule 308 (HOH308), which in turn was bound by Phe114 and Tyr90).…”

Section: Resultsmentioning

confidence: 99%

“…For sEH the PDB entry 6hgv 28 was selected as crystal structure for docking. The bound inhibitor (R)-talinolol was extracted from the structure and its binding site was used to define the docking site in a 6 Å radius.…”

Section: Methodsmentioning

confidence: 99%

“…For FLAP the recently published pdb entry 6vgc 28 with a resolution of 2.37 Å, co-crystallised with (2 R)-cyclopentyl{4-[(quinolin-2-yl)methoxy]phenyl}acetic acid (DG-031) was selected (A chain). Redocking was performed to find optimal docking settings.…”

Section: Methodsmentioning

confidence: 99%

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Synthesis and structure–activity relationships for some novel diflapolin derivatives with benzimidazole subunit

Vieider

Zoeller

Romp³

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of derivatives of the potent dual soluble epoxide hydrolase (sEH)/5-lipoxygenase-activating protein (FLAP) inhibitor diflapolin was designed, synthesised, and characterised. These novel compounds, which contain a benzimidazole subunit were evaluated for their inhibitory activity against sEH and FLAP. Molecular modelling tools were applied to analyse structure–activity relationships (SAR) on both targets and to predict solubility and gastrointestinal (GI) absorption. The most promising dual inhibitors of these series are 5a , 6b, and 6c .

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis and structure–activity relationships for some novel diflapolin derivatives with benzimidazole subunit

Vieider

Zoeller

Romp³

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…The RMSD value on heavy ligand atoms of the co-crystallized ligand of the selected crystal structure was found to be 0.48 by comparing the co-crystallized and docked poses. Similarly, binding poses of both compounds were computationally retrieved by docking within the FLAP binding site (PDB code 6WGC) . The used crystal exhibits the best resolution within published FLAP crystals, giving reproducible results with docking.…”

Section: Experimental Sectionmentioning

confidence: 99%

“…Tertiary amide counterparts of 34 prepared with cyclic amines such as piperazine (48), piperidine (49), and morpholine (50) were also inactive against sEH (IC 50 > 10 μM), suggesting that the presence of an amide NH with H-bond donor properties is important for the observed sEH inhibitory potency.…”

Section: Biological Evaluation and Sarmentioning

confidence: 99%

Quinazoline-4(3H)-one-7-carboxamide Derivatives as Human Soluble Epoxide Hydrolase Inhibitors with Developable 5-Lipoxygenase Activating Protein Inhibition

et al. 2022

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Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs), which are endowed with beneficial biological activities as they reduce inflammation, regulate endothelial tone, improve mitochondrial function, and decrease oxidative stress. Therefore, inhibition of sEH for maintaining high EET levels is implicated as a new therapeutic modality with broad clinical applications for metabolic, renal, and cardiovascular disorders. In our search for new sEH inhibitors, we designed and synthesized novel amide analogues of the quinazolinone-7carboxylic acid derivative 5, a previously discovered 5-lipoxygenase-activating protein (FLAP) inhibitor, to evaluate their potential for inhibiting sEH. As a result, we identified new quinazolinone-7-carboxamides that demonstrated selective sEH inhibition with decreased FLAP inhibitor properties. The tractable SAR results indicated that the amide and thiobenzyl fragments flanking the quinazolinone nucleus are critical features governing the potent sEH inhibition, and compounds 34, 35, 37, and 43 inhibited the sEH activity with IC 50 values of 0.30−0.66 μM. Compound 34 also inhibited the FLAP-mediated leukotriene biosynthesis (IC 50 = 2.91 μM). In conclusion, quinazolinone-7-carboxamides can be regarded as novel lead structures, and newer analogues with improved efficiency against sEH along with or without FLAP inhibition can be generated.

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Identification of 2,4‐Dinitro‐Biphenyl‐Based Compounds as MAPEG Inhibitors

et al. 2022

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We identified 2,4‐dinitro‐biphenyl‐based compounds as new inhibitors of leukotriene C4 synthase (LTC4S) and 5‐lipoxygenase‐activating protein (FLAP), both members of the “Membrane Associated Proteins in Eicosanoid and Glutathione metabolism” (MAPEG) family involved in the biosynthesis of pro‐inflammatory eicosanoids. By molecular docking we evaluated the putative binding against the targets of interest, and by applying cell‐free and cell‐based assays we assessed the inhibition of LTC4S and FLAP by the small molecules at low micromolar concentrations. The present results integrate the previously observed inhibitory profile of the tested compounds against another MAPEG member, i. e., microsomal prostaglandin E2 synthase (mPGES)‐1, suggesting that the 2,4‐dinitro‐biphenyl scaffold is a suitable molecular platform for a multitargeting approach to modulate pro‐inflammatory mediators in inflammation and cancer treatment.

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Structure-based, multi-targeted drug discovery approach to eicosanoid inhibition: Dual inhibitors of mPGES-1 and 5-lipoxygenase activating protein (FLAP)

Cited by 12 publications

References 40 publications

Synthesis and structure–activity relationships for some novel diflapolin derivatives with benzimidazole subunit

Synthesis and structure–activity relationships for some novel diflapolin derivatives with benzimidazole subunit

Quinazoline-4(3H)-one-7-carboxamide Derivatives as Human Soluble Epoxide Hydrolase Inhibitors with Developable 5-Lipoxygenase Activating Protein Inhibition

Identification of 2,4‐Dinitro‐Biphenyl‐Based Compounds as MAPEG Inhibitors

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