| Structural highlights
6vl4 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| Ligands: | , , |
NonStd Res: | |
Gene: | PTGES, MGST1L1, MPGES1, PGES, PIG12 (HUMAN) |
Activity: | Prostaglandin-E synthase, with EC number 5.3.99.3 |
Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[PTGES_HUMAN] Catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2).[1]
Publication Abstract from PubMed
BACKGROUND: Due to the importance of both prostaglandins (PGs) and leukotrienes (LTs) as pro-inflammatory mediators, and the potential for eicosanoid shunting in the presence of pathway target inhibitors, we have investigated an approach to inhibiting the formation of both PGs and LTs as part of a multi-targeted drug discovery effort. METHODS: We generated ligand-protein X-ray crystal structures of known inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1) and the 5-Lipoxygenase Activating Protein (FLAP), with their respective proteins, to understand the overlapping pharmacophores. We subsequently used molecular modeling and structure-based drug design (SBDD) to identify hybrid structures intended to inhibit both targets. RESULTS: This work enabled the preparation of compounds 4 and 5, which showed potent in vitro inhibition of both targets. SIGNIFICANCE: Our findings enhance the structural understanding of mPGES-1 and FLAP's unique ligand binding pockets and should accelerate the discovery of additional dual inhibitors for these two important integral membrane protein drug targets.
Structure-based, multi-targeted drug discovery approach to eicosanoid inhibition: Dual inhibitors of mPGES-1 and 5-lipoxygenase activating protein (FLAP).,Ho JD, Lee MR, Rauch CT, Aznavour K, Park JS, Luz JG, Antonysamy S, Condon B, Maletic M, Zhang A, Hickey MJ, Hughes NE, Chandrasekhar S, Sloan AV, Gooding K, Harvey A, Yu XP, Kahl SD, Norman BH Biochim Biophys Acta Gen Subj. 2020 Nov 25;1865(2):129800. doi:, 10.1016/j.bbagen.2020.129800. PMID:33246032[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Jegerschold C, Pawelzik SC, Purhonen P, Bhakat P, Gheorghe KR, Gyobu N, Mitsuoka K, Morgenstern R, Jakobsson PJ, Hebert H. Structural basis for induced formation of the inflammatory mediator prostaglandin E2. Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11110-5. Epub 2008 Aug 5. PMID:18682561 doi:0802894105
- ↑ Ho JD, Lee MR, Rauch CT, Aznavour K, Park JS, Luz JG, Antonysamy S, Condon B, Maletic M, Zhang A, Hickey MJ, Hughes NE, Chandrasekhar S, Sloan AV, Gooding K, Harvey A, Yu XP, Kahl SD, Norman BH. Structure-based, multi-targeted drug discovery approach to eicosanoid inhibition: Dual inhibitors of mPGES-1 and 5-lipoxygenase activating protein (FLAP). Biochim Biophys Acta Gen Subj. 2020 Nov 25;1865(2):129800. doi:, 10.1016/j.bbagen.2020.129800. PMID:33246032 doi:http://dx.doi.org/10.1016/j.bbagen.2020.129800
|