Diacylglycerol kinase (DGK or DAGK) is a family of enzymes that convert diacylglycerol to phosphatidic acid and regulate many enzymes, including protein kinase C, phosphatidylinositol 4-phosphate 5-kinase, and mTOR. Several DGK isozymes can serve as potential drug targets for a wide variety of diseases (cancer, autoimmune diseases, epilepsy, type II diabetes, cardiac hypertrophy, and hypertension) [1].
To date, ten mammalian DGK subtypes have been cloned and divided into five groups, showing subtype-specific tissue distribution [2]. The ten DGK isoforms identified so far are divided into five principal subtypes based on the organization of structural motifs: type1 (DGK-alpha, DGK-beta, DGK-gamma), type2 (DGK-delta, DGK-eta, DGK-kappa), type3 (DGK-epsilon), type4 (DGK-zeta, DGK-iota), type5 (DGK-theta) [3]. Type3, type4, and type5 have similar catalytic domains.
At Life Chemicals, we have designed a new unique Screening Library of potential diacylglycerol kinase modulators to boost the development of DGK isozyme-specific inhibitors or activators. It contains over 3,500 structurally-diverse drug-like screening compounds targeting DGK-alpha and DGK-delta enzymes, carefully selected with high-throughput virtual screening against the proprietary HTS Compound Collection.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Compound selection
To create these dedicated DGK-targeted Screening Sets, prediction of probable binding sites and protein-ligand docking were carried out against the HTS Compound Collection. Structures were also filtered using the QikProp descriptors of the Maestro Software. In-house MedChem filters were applied to provide the final selection of drug-like screening compounds targeting DGK alpha and DGK delta.
Diacylglycerol kinase alpha
DGK alpha is an enzyme that catalyzes the conversion of diacylglycerol to phosphatidic acid, thus regulating the level of these substances in the cell [4]. Diacylglycerol kinase alpha acts as a central switch between signaling pathways activated by secondary messengers such as DAG and phosphatidic acid [4]. Also, diacylglycerol kinase alpha can phosphorylate 1-alkyl-2-acylglycerol, which is involved in the synthesis of alkyl-lysophosphatidic acid [5]. Diacylglycerol kinase alpha may be an important target for treating a variety of cancers, such as melanoma, hepatocellular carcinoma, and glioblastoma, as diacylglycerol kinase is an anti-apoptotic factor [6].
Key features:
- Method: high-throughput virtual screening (docking), molecular fitting
- X-Ray data used: 6IIE
- Constraints: no
- Filters used: PAINS, toxic, reactive
- Number of compounds selected: 2,150
Fig. 1. Compound F0192-0179 in site1 diacylglycerol kinase alpha. The complex has been obtained with molecular docking.
Diacylglycerol kinase delta
DGK delta is an enzyme that catalyzes the conversion of diacylglycerol to phosphatidate. Diacylglycerol kinase delta regulates the activity of signaling pathways involving DAG and phosphatidate as secondary messengers [7]. It also regulates the functioning of PKC and EGF receptors and clathrin-dependent endocytosis [8-9]. It is established that high levels of diacylglycerol kinase delta can affect the enhancement of glucose uptake by cells. Thus, this enzyme may be an important target for the treatment or improvement of patients with type 2 diabetes [10].
Key features:
- Method: high-throughput virtual screening (docking), molecular fitting
- X-Ray data used: 3BQ7
- Constraints: no
- Filters used: PAINS, toxic, reactive
- Number of compounds selected: 1,460
Fig. 2. Compound F6416-6947 in diacylglycerol kinase delta. The complex has been obtained with molecular docking.
References:
- Sakane F, Mizuno S, Komenoi S. Diacylglycerol Kinases as Emerging Potential Drug Targets for a Variety of Diseases: An Update. Front Cell Dev Biol. 2016 Aug 17;4:82. doi: 10.3389/fcell.2016.00082. PMID: 27583247; PMCID: PMC4987324.
- Shirai Y, Saito N. Diacylglycerol kinase as a possible therapeutic target for neuronal diseases. J Biomed Sci. 2014;21(1):28. Published 2014 Apr 7. doi:10.1186/1423-0127-21-28
- Franks CE, Campbell ST, Purow BW, Harris TE, Hsu KL. The Ligand Binding Landscape of Diacylglycerol Kinases. Cell Chem Biol. 2017;24(7):870-880.e5. doi:10.1016/j.chembiol.2017.06.007
- Epand RM, Kam A, Bridgelal N, Saiga A, Topham MK. The alpha isoform of diacylglycerol kinase exhibits arachidonoyl specificity with alkylacylglycerol. Biochemistry. 2004;43(46):14778-14783. doi:10.1021/bi0484724
- Shulga YV, Topham MK, Epand RM. Study of arachidonoyl specificity in two enzymes of the PI cycle. J Mol Biol. 2011;409(2):101-112. doi:10.1016/j.jmb.2011.03.071
- Bozelli JC Jr, Epand RM. DGKα, Bridging Membrane Shape Changes with Specific Molecular Species of DAG/PA: Implications in Cancer and Immunosurveillance. Cancers (Basel). 2022;14(21):5259. Published 2022 Oct 26. doi:10.3390/cancers14215259
- Sakane F, Imai S, Yamada K, Murakami T, Tsushima S, Kanoh H. Alternative splicing of the human diacylglycerol kinase delta gene generates two isoforms differing in their expression patterns and in regulatory functions. J Biol Chem. 2002;277(45):43519-43526. doi:10.1074/jbc.M206895200
- Sato M, Liu K, Sasaki S, et al. Evaluations of the selectivities of the diacylglycerol kinase inhibitors R59022 and R59949 among diacylglycerol kinase isozymes using a new non-radioactive assay method. Pharmacology. 2013;92(1-2):99-107. doi:10.1159/000351849
- Kawasaki T, Kobayashi T, Ueyama T, Shirai Y, Saito N. Regulation of clathrin-dependent endocytosis by diacylglycerol kinase delta: importance of kinase activity and binding to AP2alpha. Biochem J. 2008;409(2):471-479. doi:10.1042/BJ20070755
- Iwata K, Sakai H, Takahashi D, Sakane F. Myristic acid specifically stabilizes diacylglycerol kinase δ protein in C2C12 skeletal muscle cells. Biochim Biophys Acta Mol Cell Biol Lipids. 2019;1864(7):1031-1038. doi:10.1016/j.bbalip.2019.04.003