Glycerol-3-phosphate phosphatase (G3PP or PGP) is a recently discovered enzyme at the heart of metabolism. It belongs to the halogen acid dehalogenase (HAD)-like hydrolase superfamily and is involved in glucose, lipid, and energy metabolism. PGP catalyzes the hydrolysis reaction of glycerol-3-phosphate, an intermediate product of the above processes, to glycerol, thus, regulating the level of glycerol-3-phosphate in the cell [1].
The role of PGP may be of key importance in metabolic disorder development, such as type 2 diabetes and obesity connected to cardiometabolic diseases. PGP activity in pancreatic β-cells reduces insulin levels, preventing hyperinsulinemia, which causes β-cell depletion and subsequent destruction [2, 3]. In the liver, increased PGP levels enhance fatty acid oxidation and reduce glucose production, with positive effects for people with type 2 diabetes and obesity [4, 5]. PGP counteracts excessive fat accumulation in the heart muscle in patients with diabetic cardiomyopathy and heart failure [6]. Therefore, PGP/G3PP is considered a promising target for the development of novel drugs against age-related metabolic disorders and lipid metabolism disorders associated with the cleavage of glycerol-3-phosphate to glycerol. Currently, there is no data on active small molecules targeting PGP due to the lack of crystallographic data on the spatial structure of this phosphatase.
Keeping pace with current and promising drug discovery R & D trends, our cheminformatics team has developed a new unique Screening Compound Library of glycerol-3-phosphate phosphatase modulators of over 2,000 structurally-diverse small molecules. For this purpose, de novo reconstruction of the spatial structure, prediction of binding sites, and protein-ligand docking was carried out. The resulting structures were also filtered based on the QikProp descriptors of the Maestro Software. The in-house MedChem, ADME, as well as PAINS filters, were applied to the selected structures to provide only drug-like screening compounds.
The compound selection can be customized based on your requirements, cherry picking is available.
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Compound selection
Reconstructions of the human PGP protein from the A6NDG6 sequence were performed in AlphaFold, Robetta and I-TASSER (Fig. 1). The quality of the models was evaluated in MolProbity. For each of the models, five sites were built and docking was carried out in all five sites of the three models (Fig. 2). The resulting compound sets, obtained with the “by site” approach, were combined with model ones and then compared among themselves (Fig. 3). The resulting libraries were shortened according to QikProp properties and descriptors in Schrödinger Software.
As a result, over 2,000 unique drug-like molecules that are potential PGP inhibitors were selected for this Screening Compound Library.
Figure 1. Reconstructions of the human PGP protein from the A6NDG6 sequence: structural alignment of the obtained models (green - Robetta reconstruction, blue - AlphaFold reconstruction, yellow - I-TASSER reconstruction).
Figure 2. Binding sites on the surface of the PGP protein.
Figure 3. Compound (F6436-3707) in site 1 of the Robetta model. The complex has been obtained with molecular docking.
References:
- Mugabo Y, Zhao S, Seifried A, et al. Identification of a mammalian glycerol-3-phosphate phosphatase: Role in metabolism and signaling in pancreatic β-cells and hepatocytes. Proc Natl Acad Sci U S A. 2016;113(4):E430-E439. doi:10.1073/pnas.1514375113
- Possik E, Al-Mass A, Peyot ML, et al. New Mammalian Glycerol-3-Phosphate Phosphatase: Role in β-Cell, Liver and Adipocyte Metabolism. Front Endocrinol (Lausanne). 2021;12:706607. Published 2021 Jul 13. doi:10.3389/fendo.2021.706607
- El-Assaad W, Buteau J, Peyot ML, et al. Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death. Endocrinology. 2003;144(9):4154-4163. doi:10.1210/en.2003-0410
- Prentki M, Corkey BE. Are the beta-cell signaling molecules malonyl-CoA and cystolic long-chain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM?. Diabetes. 1996;45(3):273-283. doi:10.2337/diab.45.3.273
- Ho-Palma AC, Toro P, Rotondo F, et al. Insulin Controls Triacylglycerol Synthesis through Control of Glycerol Metabolism and Despite Increased Lipogenesis. Nutrients. 2019;11(3):513. Published 2019 Feb 28. doi:10.3390/nu11030513
- Rotondo F, Ho-Palma AC, Remesar X, Fernández-López JA, Romero MDM, Alemany M. Glycerol is synthesized and secreted by adipocytes to dispose of excess glucose, via glycerogenesis and increased acyl-glycerol turnover. Sci Rep. 2017;7(1):8983. Published 2017 Aug 21. doi:10.1038/s41598-017-09450-4