Chemical and Protein Structural Basis for Biological Crosstalk Between PPARα and COX Enzymes

Overview

Journal J Comput Aided Mol Des

Publisher Springer

Specialties Biomedical Engineering
Molecular Biology

Date 2014 Nov 28

PMID 25428568

Citations 6

Authors

Ann E Cleves

Ajay N Jain

Affiliations

Soon will be listed here.

Abstract

We have previously validated a probabilistic framework that combined computational approaches for predicting the biological activities of small molecule drugs. Molecule comparison methods included molecular structural similarity metrics and similarity computed from lexical analysis of text in drug package inserts. Here we present an analysis of novel drug/target predictions, focusing on those that were not obvious based on known pharmacological crosstalk. Considering those cases where the predicted target was an enzyme with known 3D structure allowed incorporation of information from molecular docking and protein binding pocket similarity in addition to ligand-based comparisons. Taken together, the combination of orthogonal information sources led to investigation of a surprising predicted relationship between a transcription factor and an enzyme, specifically, PPARα and the cyclooxygenase enzymes. These predictions were confirmed by direct biochemical experiments which validate the approach and show for the first time that PPARα agonists are cyclooxygenase inhibitors.

Citing Articles

Design, synthesis, pharmacological evaluation, and studies of the activity of novel spiro pyrrolo[3,4-]pyrimidine derivatives.

Y A Alzahrani A, Shehab W, Amer A, Assy M, Mouneir S, Aziz M RSC Adv. 2024; 14(2):995-1008.

PMID: 38174254 PMC: 10759174. DOI: 10.1039/d3ra07078f.

Estimating the Similarity between Protein Pockets.

Eguida M, Rognan D Int J Mol Sci. 2022; 23(20).

PMID: 36293316 PMC: 9604425. DOI: 10.3390/ijms232012462.

Practical approaches to adverse outcome pathway development and weight-of-evidence evaluation as illustrated by ecotoxicological case studies.

Fay K, Villeneuve D, LaLone C, Song Y, Tollefsen K, Ankley G Environ Toxicol Chem. 2017; 36(6):1429-1449.

PMID: 28198554 PMC: 6058314. DOI: 10.1002/etc.3770.

Extrapolative prediction using physically-based QSAR.

Cleves A, Jain A J Comput Aided Mol Des. 2016; 30(2):127-52.

PMID: 26860112 PMC: 4796382. DOI: 10.1007/s10822-016-9896-1.

Modeling enzyme-ligand binding in drug discovery.

Konc J, Lesnik S, Janezic D J Cheminform. 2015; 7(1):48.

PMID: 26457119 PMC: 4594084. DOI: 10.1186/s13321-015-0096-0.

References

Goedken E, Gagnon A, Overmeyer G, Liu J, Petrillo R, Burchat A . HTRF-based assay for microsomal prostaglandin E2 synthase-1 activity. J Biomol Screen. 2008; 13(7):619-25. DOI: 10.1177/1087057108321145. View

Gugler R, Hartlapp J . Clofibrate kinetics after single and multiple doses. Clin Pharmacol Ther. 1978; 24(4):432-8. DOI: 10.1002/cpt1978244432. View

Schwarz R, Tanzler D, Ihling C, Muller M, Kolbel K, Sinz A . Monitoring conformational changes in peroxisome proliferator-activated receptor α by a genetically encoded photoamino acid, cross-linking, and mass spectrometry. J Med Chem. 2013; 56(11):4252-63. DOI: 10.1021/jm400446b. View

Smith W, Dewitt D, Garavito R . Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem. 2000; 69:145-82. DOI: 10.1146/annurev.biochem.69.1.145. View

Daynes R, Jones D . Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol. 2002; 2(10):748-59. DOI: 10.1038/nri912. View

Jain A . Surflex: fully automatic flexible molecular docking using a molecular similarity-based search engine. J Med Chem. 2003; 46(4):499-511. DOI: 10.1021/jm020406h. View

Cleves A, Jain A . Robust ligand-based modeling of the biological targets of known drugs. J Med Chem. 2006; 49(10):2921-38. DOI: 10.1021/jm051139t. View

Spitzer R, Cleves A, Varela R, Jain A . Protein function annotation by local binding site surface similarity. Proteins. 2013; 82(4):679-94. PMC: 3949165. DOI: 10.1002/prot.24450. View

Budd A, Alleva L, Alsharifi M, Koskinen A, Smythe V, Mullbacher A . Increased survival after gemfibrozil treatment of severe mouse influenza. Antimicrob Agents Chemother. 2007; 51(8):2965-8. PMC: 1932503. DOI: 10.1128/AAC.00219-07. View

10.

Delerive P, Fruchart J, Staels B . Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol. 2001; 169(3):453-9. DOI: 10.1677/joe.0.1690453. View

11.

Riendeau D, Charleson S, Cromlish W, Mancini J, Wong E, Guay J . Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays. Can J Physiol Pharmacol. 1997; 75(9):1088-95. View

12.

Yera E, Cleves A, Jain A . Prediction of off-target drug effects through data fusion. Pac Symp Biocomput. 2013; :160-71. PMC: 3897331. View

13.

Keiser M, Setola V, Irwin J, Laggner C, Abbas A, Hufeisen S . Predicting new molecular targets for known drugs. Nature. 2009; 462(7270):175-81. PMC: 2784146. DOI: 10.1038/nature08506. View

14.

Kurumbail R, Stevens A, Gierse J, McDonald J, Stegeman R, Pak J . Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996; 384(6610):644-8. DOI: 10.1038/384644a0. View

15.

Keiser M, Roth B, Armbruster B, Ernsberger P, Irwin J, Shoichet B . Relating protein pharmacology by ligand chemistry. Nat Biotechnol. 2007; 25(2):197-206. DOI: 10.1038/nbt1284. View

16.

Backman J, Kyrklund C, Kivisto K, Wang J, Neuvonen P . Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther. 2000; 68(2):122-9. DOI: 10.1067/mcp.2000.108507. View

17.

Jain A . Morphological similarity: a 3D molecular similarity method correlated with protein-ligand recognition. J Comput Aided Mol Des. 2000; 14(2):199-213. DOI: 10.1023/a:1008100132405. View

18.

Bai H, Zhu B . Strong activation of cyclooxygenase I and II catalytic activity by dietary bioflavonoids. J Lipid Res. 2008; 49(12):2557-70. PMC: 2582366. DOI: 10.1194/jlr.M800358-JLR200. View

19.

Glaser K, Sung M, ONeill K, Belfast M, Hartman D, Carlson R . Etodolac selectively inhibits human prostaglandin G/H synthase 2 (PGHS-2) versus human PGHS-1. Eur J Pharmacol. 1995; 281(1):107-11. DOI: 10.1016/0014-2999(95)00302-2. View

20.

Santin J, Uchoa F, Lima M, Rabello M, Daufenback Machado I, Hernandes M . Chemical synthesis, docking studies and biological effects of a pan peroxisome proliferator-activated receptor agonist and cyclooxygenase inhibitor. Eur J Pharm Sci. 2013; 48(4-5):689-97. DOI: 10.1016/j.ejps.2012.12.029. View