Discovery of Novel Soluble Epoxide Hydrolase Inhibitors as Potent Vasodilators.

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.

• Authors: Neetika Tripathi, Sarvesh Paliwal, Swapnil Sharma, Kanika Verma, Ritika Gururani, Akanksha Tiwari, Amrita Verma, Monika Chauhan, Aarti Singh, Dipak Kumar, Aditya Pant
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 14604 (10 02 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 30279487 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Recombinant Proteins
• Vasodilator Agents
• Epoxide Hydrolases
• EPHX2 protein, human

Topics

• Amino Acid Motifs
• Animals
• Aorta (drug effects, physiology)
• Catalytic Domain
• Cell Survival (drug effects)
• Drug Discovery
• Enzyme Assays
• Enzyme Inhibitors (chemistry, pharmacology)
• Epoxide Hydrolases (antagonists & inhibitors, chemistry, metabolism)
• Humans
• Hydrogen Bonding
• Hydrophobic and Hydrophilic Interactions
• Male
• Mesenchymal Stem Cells (cytology, drug effects, physiology)
• Molecular Docking Simulation
• Rats
• Rats, Wistar
• Recombinant Proteins (chemistry, metabolism)
• Structure-Activity Relationship
• Tissue Culture Techniques
• Vasodilation (drug effects)
• Vasodilator Agents (chemistry, pharmacology)