SAR Study And Drug-likeness Prediction Of Celastrol Derivatives Targeting Orphan Nuclear Receptor Nur77

As a member of the nuclear receptor superfamily,the orphan nuclear receptor Nur77 is a key regulator of cell proliferation,differentiation and apoptosis and is inmplicated in cancer,metabolism and inflammatory diseases.Celastrol,as an extract from the root and bark of Tripterygium wilfordii,has a variety of biological activities.Our group found that celastrol can bind to Nur77,induce the localization of Nur77 from nucleus to mitochondria where it interacts with TRAF2.This process results in the ubiquitination of Nur77,the inhibitition of TRAF2 ubiquitination,and the interaction between the ubiquitinated Nur77 and p62 protein,which subsequently induce mitochondrial autophagy of inflammatory cells and exert anti-inflammatory activity.Hence,we hope to develop Celastrol as a drug targeting Nur77.However,the specific interaction mechanism of celastrol with Nur77 is still unclear,and the key groups enabling the Nur77 binding ability of celastrol remain to be explored.To optim ize the structure,we have modified the key groups that may contribute to the celastrol binding with Nur77-LBD and to establish some preliminary understanding of the structure-activity relationship.This study synthesized and characterized 27 derivatives of Celastrol,including 5 esterification and amidation of C20 carboxyl group,10 reduction and addition products on C6 position,2 modifications of C3 position while retaining their quinone methide structure,10 products in which the hydroxyl groups are selectively alkylated based on the reduction of C6 position of Celastrol.Through SPR binding studies we found that(1)Modification of the C20 position of Celastrol could increase Kd slightly showing little effect on the binding ability;(2)Except for the reduction product XS0419,all modifications on C6 would weaken the binding significantly;(3)Further modification of the A-ring on the reduction product of Celastrol C6 would result in the loss of binding ability.Furthermore,this study applied ADME/Tox predictions to analyze the druglikeness properties of the above synthesized derivatives and derive some preliminary conclusions that may facilitate subsequent modification.For example,groups of appropriate sizes that would help to improve solubility should be introduced at suitable positions,such as carboxyl group or C6 position.And excessive alkylation modification is unsuitable because it would cause a decrease in the solubility or oral availability.