Identification of non-lipid LPA3 antagonists by virtual screening

Fells, James I.; Tsukahara, Ryoko; Fujiwara, Yuko; Liu, Jianxiong; Perygin, Donna H.; Osborne, Daniel A.; Tigyi, Gábor; Parrill, Abby L.

doi:10.1016/j.bmc.2008.04.035

Cited by 30 publications

(25 citation statements)

References 36 publications

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“…These compounds are weak inhibitors with relatively poor efficacy and are nonselective LPA 5 antagonists; however, they provide a valuable starting point for similarity searches and synthetic improvements to optimize the substituent identity and placement on a scaffold already known to provide biological activity. The scaffold defines the overall shape, but differences in electrostatic distribution and localized shape features can produce drastic improvements in potency, efficacy, and selectivity as we have observed in our optimization of LPA 3 receptor antagonists (46).…”

Section: Discussionmentioning

confidence: 69%

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Williams

Khandoga²,

Goyal³

et al. 2009

Journal of Biological Chemistry

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140

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Lysophosphatidic acid (LPA) is a ligand for LPA 1-3 of the endothelial differentiation gene family G-protein-coupled receptors, and LPA 4 -8 is related to the purinergic family G-protein-coupled receptor. Because the structure-activity relationship (SAR) of GPR92/LPA 5 is limited and whether LPA is its preferred endogenous ligand has been questioned in the literature, in this study we applied a combination of computational and experimental site-directed mutagenesis of LPA 5 residues predicted to interact with the headgroup of LPA. Four residues involved in ligand recognition in LPA 5 were identified as follows: R2.60N mutant abolished receptor activation, whereas H4.64E, R6.62A, and R7.32A greatly reduced receptor activation. We also investigated the SAR of LPA 5 using LPA analogs and other non-lysophospholipid ligands. SAR revealed that the rank order of agonists is alkyl glycerol phosphate > LPA > farnesyl phosphates Ͼ Ͼ N-arachidonoylglycine. These results confirm LPA 5 to be a bona fide lysophospholipid receptor. We also evaluated several compounds with previously established selectivity for the endothelial differentiation gene receptors and found several that are LPA 5 agonists. A pharmacophore model of LPA 5 binding requirements was developed for in silico screening, which identified two non-lipid LPA 5 antagonists. Because LPA 5 transcripts are abundant in human platelets, we tested its antagonists on platelet activation and found that these non-lipid LPA 5 antagonists inhibit platelet activation. The present results suggest that selective inhibition of LPA 5 may provide a basis for future anti-thrombotic therapies.Lysophosphatidic acid (LPA, 2 1-radyl-2-hydroxy-sn-3-glycero phosphate) specifically interacts with several protein targets that regulate physiological and pathophysiological processes (1-3). LPA targets include specific G-protein-coupled receptors (GPCRs) that mediate a wide variety of biological effects, including cell proliferation (4), cell survival (5), cell migration (6), and platelet aggregation (7,8). GPCRs are the largest family of transmembrane receptors and represent targets of many therapeutics (9). Eight LPA-specific mammalian GPCRs, LPA 1-8 , have been identified to date (10 -12). Among the eight LPA receptors, LPA 1 , LPA 2 , and LPA 3 are members of the endothelial differentiation gene (EDG) family (13), and the transmembrane domains of human LPA 1-3 show 81% homology with each other (14). The five other members of the EDG family are specific for the related lysophospholipid sphingosine 1-phosphate (S1P). The structural foundation for LPA selectivity over S1P has been linked to a single amino acid at position 3.29, a conserved glutamine in the LPA-specific and glutamate in the S1P-specific members of the EDG family (14 -16). However, the recently identified non-EDG family LPA receptors, LPA 4 /p2y9 (13), LPA 5 /GPR92 (17, 18), LPA 6 /GPR87 (19), LPA 7 /p2y5 (12), and LPA 8 /p2y10 (10), are more closely related to the purinoreceptor gene cluster and share less than 20% amino acid...

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Section: Discussionmentioning

confidence: 69%

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Williams

Khandoga²,

Goyal³

et al. 2009

Journal of Biological Chemistry

Self Cite

140

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“…Antagonist activity at a specific receptor could be counterbalanced by agonist or partial agonist activity at a different receptor, as was observed early on with fatty alkyl phosphates [51]. In silico screening using a validated model of the LPA 3 receptor produced lead non-lipid antagonists containing an indole ring system [52]. Similarity searching based on the initial lead filtered based on docking studies produced a high proportion of active compounds, 10 of 16 compounds screened, with 9 of the actives showing greater effect at 10 μM than the lead [53].…”

Section: Antagonist Sarmentioning

confidence: 94%

Design of Anticancer Lysophosphatidic Acid Agonists and Antagonists

Parrill¹

2014

Future Med. Chem.

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Lysophosphatidic acid (LPA) and its receptors, LPA1-6, are integral parts of signaling pathways involved in cellular proliferation, migration and survival. These signaling pathways are of therapeutic interest for the treatment of multiple types of cancer and to reduce cancer metastasis and side effects. Validated therapeutic potential of key receptors, as well as recent structure-activity relationships yielding compounds with low nanomolar potencies are exciting recent advances in the field. Some compounds have proven efficacious in vivo against tumor proliferation and metastasis, bone cancer pain and the pulmonary fibrosis that can result as a side effect of pulmonary cancer radiation treatment. However, recent studies have identified that LPA contributes through multiple pathways to the development of chemotherapeutic resistance suggesting new applications for LPA antagonists in cancer treatment. This review summarizes the roles of LPA signaling in cancer pathophysiology and recent progress in the design and evaluation of LPA agonists and antagonists.

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“…Inositol phosphate production 5987411 [121] 1400 3500 Calcium mobilization NSC161613 [122] 24 Calcium mobilization H2L5186303 [122] 27354 9 1230…”

Section: Lpa As a Profibrotic Mediator 41 Renal Fibrosismentioning

confidence: 99%