Characterization of crystal water molecules in a high-affinity inhibitor and hematopoietic prostaglandin D synthase complex by interaction energy studies

Takaya, Daisuke; Inaka, Koji; Omura, Akifumi; Takenuki, Kenji; Kawanishi, Masashi; Yabuki, Yukako; Nakagawa, Yukari; Tsuganezawa, Keiko; Ogawa, Naoko; Watanabe, Chiduru; Honma, Teruki; Aritake, Kosuke; Urade, Yoshihiro; Shirouzu, Mikako; Tanaka, Akiko

doi:10.1016/j.bmc.2018.08.014

Cited by 17 publications

(15 citation statements)

References 34 publications

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“…Other investigators also have noted the significance of PGDS inhibitor interactions with the conserved water that associates with C-terminal Leu199 (Aritake et al 2006;Hohwy et al 2008;Carron et al 2010;Edfeldt et al 2015). Further studies supported the role of water molecules in the active site of hPGDS in substrate and GSH binding (Takaya et al 2018). Substructure analysis of PGDS inhibitors indicated that a phenyl group, a heterocyclic group, e.g.…”

Section: Theta-class (Gstt)mentioning

confidence: 87%

The mercapturic acid pathway

Hanna

Anders

2019

Critical Reviews in Toxicology

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The mercapturic acid pathway is a major route for the biotransformation of xenobiotic and endobiotic electrophilic compounds and their metabolites. Mercapturic acids (N-acetyl-L-cysteine S-conjugates) are formed by the sequential action of the glutathione transferases, c-glutamyltransferases, dipeptidases, and cysteine S-conjugate N-acetyltransferase to yield glutathione S-conjugates, L-cysteinylglycine S-conjugates, L-cysteine S-conjugates, and mercapturic acids; these metabolites constitute a "mercapturomic" profile. Aminoacylases catalyze the hydrolysis of mercapturic acids to form cysteine S-conjugates. Several renal transport systems facilitate the urinary elimination of mercapturic acids; urinary mercapturic acids may serve as biomarkers for exposure to chemicals. Although mercapturic acid formation and elimination is a detoxication reaction, L-cysteine S-conjugates may undergo bioactivation by cysteine Sconjugate b-lyase. Moreover, some L-cysteine S-conjugates, particularly L-cysteinyl-leukotrienes, exert significant pathophysiological effects. Finally, some enzymes of the mercapturic acid pathway are described as the so-called "moonlighting proteins," catalytic proteins that exert multiple biochemical or biophysical functions apart from catalysis.

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Section: Theta-class (Gstt)mentioning

confidence: 87%

The mercapturic acid pathway

Hanna

Anders

2019

Critical Reviews in Toxicology

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“…Among the representative H-PGDS selective inhibitors, HQL-79, 16 F092, 18 BSPT, 19 TAS-204, 7 and TFC-007, TAS-204, and TFC-007 show high activity (with IC50 values of 23 and 83 nM, respectively, Figure 1a). [5][6][7][8] The binding mode between H-PGDS and F092 (and HQL-79) has been revealed by X-ray diffraction.…”

Section: Resultsmentioning

confidence: 99%

Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer

Yokoo¹,

Shibata²,

Naganuma³

et al. 2020

Preprint

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Although hematopoietic prostaglandin D synthase (H-PGDS) is an attractive target for treatment of a variety of diseases, including allergic diseases and Duchenne muscular dystrophy, no H-PGDS inhibitors have yet been approved for treatment of these diseases. Therefore, the development of novel agents having other mode of actions to modulate the activity of H-PGDS is required. In this study, a chimeric small molecule that degrades H-PGDS via the ubiquitin-proteasome system, PROTAC(H-PGDS)-1, was developed. PROTAC(H-PGDS)-1 is composed of two ligands, TFC-007 (that binds to H-PGDS) and pomalidomide (that binds to cereblon). PROTAC(H-PGDS)-1 showed potent activity in the degradation of H-PGDS protein via the ubiquitin-proteasome system and in the suppression of prostaglandin D2 (PGD2) production. Notably, PROTAC(H-PGDS)-1 was slightly more effective in the suppression of PGD2 production than the known inhibitor, TFC-007. Thus, the H-PGDS degrader—PROTAC(H-PGDS)-1—is expected to be useful in biological research and clinical therapies.

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“…Five phytochemicals showed greater ligand efficiency than the positive control glutathione. Among them, phthalic acid demonstrated the highest ligand efficiency and interacted with Arg14 and Tyr152 (H-bonds), and Arg14, Met99, and Trp104 (hydrophobic bonds) identified as key residues of the catalytic site of PGD 2 synthase [44][45][46]. Further work is required to test the hair growth-promoting effect of phthalic acid, which unlike phthalates, has a low toxicity profile [47].…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory, Thrombolytic and Hair-Growth Promoting Activity of the n-Hexane Fraction of the Methanol Extract of Leea indica Leaves

Sakib

Tareq

Islam

et al. 2021

Plants

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The anti-inflammatory, thrombolytic, and hair growth-promoting activity of the n-hexane fraction from the methanol extract of Leea indica (NFLI) leaves was investigated. NFLI showed significant inhibition of hemolysis and protein denaturation, and exhibited a concentration-dependent thrombolytic activity. When applied topically to mice at concentrations of 10, 1, 0.1%, NFLI demonstrated a significant increase in average hair length (p < 0.001) compared with untreated animals. NFLI (1% concentration) exhibited the highest percentage of hair regrowth on day 7, 14 and 21 (81.24, 65.60, and 62.5%, respectively). An in silico study was further conducted to predict the binding affinity of phytochemicals previously reported in L. indica towards PGD2 synthase (PDB ID: 2VD1), an enzyme that catalyses the isomerisation of prostaglandin H2 to PGD2 which is involved in hair loss. Phthalic acid, farnesol, n-tricosane, n-tetracosane, and n-heptacosane showed the best ligand efficiencies towards PGD2 synthase and their intermolecular interactions were visualised using BIOVIA Discovery Studio Visualizer. Our results indicate that L. indica could represent a promising natural alternative to tackle alopecia.

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Characterization of crystal water molecules in a high-affinity inhibitor and hematopoietic prostaglandin D synthase complex by interaction energy studies

Cited by 17 publications

References 34 publications

The mercapturic acid pathway

The mercapturic acid pathway

Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer

Anti-Inflammatory, Thrombolytic and Hair-Growth Promoting Activity of the n-Hexane Fraction of the Methanol Extract of Leea indica Leaves

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