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. 2018 Oct 2;8(1):14604.
doi: 10.1038/s41598-018-32449-4.

Discovery of Novel Soluble Epoxide Hydrolase Inhibitors as Potent Vasodilators

Neetika Tripathi  1 , Sarvesh Paliwal  2 , Swapnil Sharma  1 , Kanika Verma  1 , Ritika Gururani  1 , Akanksha Tiwari  1 , Amrita Verma  1 , Monika Chauhan  1 , Aarti Singh  1 , Dipak Kumar  3 , Aditya Pant  3
Affiliations

Discovery of Novel Soluble Epoxide Hydrolase Inhibitors as Potent Vasodilators

Neetika Tripathi et al. Sci Rep. .

Abstract

In view of the role of sEH (soluble epoxide hydrolase) in hypertension, we have developed a rigorously validated pharmacophore model containing one HBA (Hydrogen Bond Acceptor), two HY (Hydrophobic) and one RA (Ring Aromatic) features. The model was used as a query to search the NCI (National Cancer Institute) and Maybridge database leading to retrieval of many compounds which were sorted on the basis of predicted activity, fit value and Lipinski's violation. The selected compounds were docked into the active site of enzyme soluble epoxide hydrolase. Potential interactions were observed between the features of the identified hits and the amino acids present in the docking site. The three selected compounds were subjected to in vitro evaluation using enzyme- based assay and the isolated rat aortic model followed by cytotoxicity studies. The results demonstrate that the identified compounds are potent, safe and novel soluble epoxide hydrolase inhibitors.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Therapeutic targets in the arachidonate cascade. Three key pathways- the cyclooxygenase (COX), Lipoxygenase (LOX) and cytochrome P450 (CYP) pathways, Epoxyeicosatrienoic acid (EET), Dihydroxyeicosatrienoic acid (DHET).
Figure 2
Figure 2
Pharmacophore with two HBA, one HY and RA features.
Figure 3
Figure 3
Observed correlation coefficient values of training set.
Figure 4
Figure 4
Most active compound of training set.
Figure 5
Figure 5
Least active compound of training set.
Figure 6
Figure 6
Fischer’s randomization test.
Figure 7
Figure 7
Observed correlation coefficient values of internal and external test set.
Figure 8
Figure 8
Most active compound of the external test set exhibit a perfect four feature mapping.
Figure 9
Figure 9
Ligand driven pharmacophore based virtual screening.
Figure 10
Figure 10
Docked conformation of NSC 10203 on the active site of soluble epoxide hydrolase.
Figure 11
Figure 11
Docked conformation of HTS 04151on the active site of soluble epoxide hydrolase.
Figure 12
Figure 12
Docked conformation of HTS 00684 on the active site of soluble epoxide hydrolase.
Figure 13
Figure 13
Concentration dependent inhibition of human sEH by compounds (a) AUDA (b) NSC 10203 (c) HTS 04151 (d) HTS 00684; n = 3.
Figure 14
Figure 14
Vasodilatory effect of (a) AUDA (b) NSC 10203 (c) HTS 04151 (d) HTS 00684 at various concentrations.
Figure 15
Figure 15
In- vitro cytotoxicity assay (a) 24 hrs (b) 48 hrs (c) 96 hrs.
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