학술논문
Synthesis, characterization and bioactivity studies of novel 1,3,4-oxadiazole small molecule that targets basic phospholipase A.sub.2 from Vipera russelli
Article
Article
Document Type
Academic Journal
Source
Molecular and Cellular Biochemistry. February 2017, Vol. 426 Issue 1-2, p161, 15 p.
Subject
Language
English
ISSN
0300-8177
Abstract
Author(s): Vivek Hamse Kameshwar [sup.1] , Kumar J. R. [sup.2] , Babu S. Priya [sup.3] , S. Nanjunda Swamy [sup.1] Author Affiliations: (1) Department of Biotechnology, JSS Science and Technology [...]
Secretory phospholipase A.sub.2 (sPLA.sub.2) is a key enzyme participating in the inflammatory cascade followed by the action of cyclooxygenase-2 and lipoxygenases. Therefore, inhibitors of sPLA.sub.2 could be used as potent anti-inflammatory agents to treat the early phase of inflammation. In this study, we have prepared the fenoprofen and ibuprofen analogs containing 1,3,4-oxadiazole nucleus and tested against Vipera russelli venom's basic sPLA.sub.2 (VRV-PL-VIIIa). Among the tested ligands 5(a-t),2-(2-chlorophenyl)-5-(1-(4-phenoxyphenyl) ethyl)-1,3,4-oxadiazole (5m) inhibited the catalytic activity of VRV-PL-VIIIa with an IC.sub.50 value of 11.52 [micro]M. Biophysical studies revealed that the 5m quenches the intrinsic fluorescence of VRV-PL-VIIIa, in a concentration dependent manner. Also, the compound 5m affected VRV-PL-VIIIa conformation, which was observed by circular dichroism spectra that recorded the prominent shift in the [alpha]-helix peak and the random coil formation of VRV-PL-VIIIa. Further, molecular docking analysis revealed that the compound 5m possess strong hydrophobic interactions at catalytic triad region of the VRV-PL-VIIIa. Evident to in vitro and in silico studies, 5m strongly inhibited the hemolysis of red blood cells. Our in vivo pharmacological studies revealed that the compound 5m inhibited the edematogenic activity of VRV-PL-VIIIa in mouse foot pad. Additionally, the 5m inhibited VRV-PL-VIIIa-induced myotoxicity and lung hemorrhage in mice. Overall, our ADMET results depicted that 5m possess better druggable property. Thus, this study explored the new fenoprofen and ibuprofen analog 5m as the lead-structure that serves as an anti-inflammatory agent.
Secretory phospholipase A.sub.2 (sPLA.sub.2) is a key enzyme participating in the inflammatory cascade followed by the action of cyclooxygenase-2 and lipoxygenases. Therefore, inhibitors of sPLA.sub.2 could be used as potent anti-inflammatory agents to treat the early phase of inflammation. In this study, we have prepared the fenoprofen and ibuprofen analogs containing 1,3,4-oxadiazole nucleus and tested against Vipera russelli venom's basic sPLA.sub.2 (VRV-PL-VIIIa). Among the tested ligands 5(a-t),2-(2-chlorophenyl)-5-(1-(4-phenoxyphenyl) ethyl)-1,3,4-oxadiazole (5m) inhibited the catalytic activity of VRV-PL-VIIIa with an IC.sub.50 value of 11.52 [micro]M. Biophysical studies revealed that the 5m quenches the intrinsic fluorescence of VRV-PL-VIIIa, in a concentration dependent manner. Also, the compound 5m affected VRV-PL-VIIIa conformation, which was observed by circular dichroism spectra that recorded the prominent shift in the [alpha]-helix peak and the random coil formation of VRV-PL-VIIIa. Further, molecular docking analysis revealed that the compound 5m possess strong hydrophobic interactions at catalytic triad region of the VRV-PL-VIIIa. Evident to in vitro and in silico studies, 5m strongly inhibited the hemolysis of red blood cells. Our in vivo pharmacological studies revealed that the compound 5m inhibited the edematogenic activity of VRV-PL-VIIIa in mouse foot pad. Additionally, the 5m inhibited VRV-PL-VIIIa-induced myotoxicity and lung hemorrhage in mice. Overall, our ADMET results depicted that 5m possess better druggable property. Thus, this study explored the new fenoprofen and ibuprofen analog 5m as the lead-structure that serves as an anti-inflammatory agent.