Pentacyclic Triterpenoids Inhibit IKK? Mediated Activation of NF-?B Pathway: In Silico and In Vitro Evidences.

ABSTRACT: Pentacyclic Triterpenoids (PTs) and their analogues as well as derivatives are emerging as important drug leads for various diseases. They act through a variety of mechanisms and a majority of them inhibit the nuclear factor kappa-beta (NF-?B) signaling pathway. In this study, we examined the effects of the naturally occurring PTs on I?B kinase-? (IKK?), which has great scientific relevance in the NF-?B signaling pathway. On virtual screening, 109 PTs were screened through the PASS (prediction of activity spectra of substances) software for prediction of NF-?B inhibitory activity followed by docking on the NEMO/IKK? association complex (PDB: 3BRV) and testing for compliance with the softened Lipinski's Rule of Five using Schrodinger (LLC, New York, USA). Out of the projected 45 druggable PTs, Corosolic Acid (CA), Asiatic Acid (AA) and Ursolic Acid (UA) were assayed for IKK? kinase activity in the cell free medium. The UA exhibited a potent IKK? inhibitory effect on the hotspot kinase assay with IC50 of 69 ?M. Whereas, CA at 50 ?M concentration markedly reduced the NF-?B luciferase activity and phospho-IKK? protein expressions. The PTs tested, attenuated the expression of the NF-?B cascade proteins in the LPS-stimulated RAW 264.7 cells, prevented the phosphorylation of the IKK?/? and blocked the activation of the Interferon-gamma (IFN-?). The results suggest that the IKK? inhibition is the major mechanism of the PTs-induced NF-?B inhibition. PASS predictions along with in-silico docking against the NEMO/IKK? can be successfully applied in the selection of the prospective NF-?B inhibitory downregulators of IKK? phosphorylation.

SUBMITTER: Patil KR 

PROVIDER: S-EPMC4418667 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature