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Identfication of Potent LXR?-Selective Agonists without LXR? Activation by In Silico Approaches.

ABSTRACT: Activating Liver X receptors (LXRs) represents a promising therapeutic option for dyslipidemia. However, activating LXR? may cause undesired lipogenic effects. Discovery of highly LXR?-selective agonists without LXR? activation were indispensable for dyslipidemia. In this study, in silico approaches were applied to develop highly potent LXR?-selective agonists based on a series of newly reported 3-(4-(2-propylphenoxy)butyl)imidazolidine-2,4-dione-based LXR?/? dual agonists. Initially, Kohonen and stepwise multiple linear regression SW-MLR were performed to construct models for LXR? agonists and LXR? agonists based on the structural characteristics of LXR?/? dual agonists, respectively. The obtained LXR? agonist model gave a good predictive ability (R²train = 0.837, R²test = 0.843, Q²LOO = 0.715), and the LXR? agonist model produced even better predictive ability (R²train = 0.968, R²test = 0.914, Q²LOO = 0.895). Also, the two QSAR models were independent and can well distinguish LXR? and LXR? activity. Then, compounds in the ZINC database met the lower limit of structural similarity of 0.7, compared to the 3-(4-(2-propylphenoxy)butyl)imidazolidine-2,4-dione scaffold subjected to our QSAR models, which resulted in the discovery of ZINC55084484 with an LXR? prediction value of pEC50 equal to 7.343 and LXR? prediction value of pEC50 equal to -1.901. Consequently, nine newly designed compounds were proposed as highly LXR?-selective agonists based on ZINC55084484 and molecular docking, of which LXR? prediction values almost exceeded 8 and LXR? prediction values were below 0.

SUBMITTER: Chen M

PROVIDER: S-EPMC6099648 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Identfication of Potent LXRβ-Selective Agonists without LXRα Activation by In Silico Approaches.

Chen Meimei M Yang Fafu F Kang Jie J Gan Huijuan H Yang Xuemei X Lai Xinmei X Gao Yuxing Y

Molecules (Basel, Switzerland) 20180604 6

Activating Liver X receptors (LXRs) represents a promising therapeutic option for dyslipidemia. However, activating LXRα may cause undesired lipogenic effects. Discovery of highly LXRβ-selective agonists without LXRα activation were indispensable for dyslipidemia. In this study, in silico approaches were applied to develop highly potent LXRβ-selective agonists based on a series of newly reported 3-(4-(2-propylphenoxy)butyl)imidazolidine-2,4-dione-based LXRα/β dual agonists. Initially, Kohonen an ...[more]

PMID: 29867043

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Project description:BACKGROUND:MAPK/ERK kinases transmit signals from many growth factors/kinase receptors during normal cell growth/differentiation, and their dysregulation is a hallmark of diverse types of cancers. A plethora of drugs were developed to block this kinase pathway for clinical application. With the exception of a recently identified agent, EQW, most of these inhibitors target upstream factors but not ERK1/2; no activator of ERK1/2 is currently available. METHOD:A library of compounds isolated from medicinal plants of China was screened for anti-cancer activities. Three limonoid compounds, termed A1541-43, originally isolated from the plant Melia azedarach, exhibiting strong anti-leukemic activity. The anti-neoplastic activity and the biological target of these compounds were explored using various methods, including western blotting, flow cytometry, molecular docking and animal model for leukemia. RESULTS:Compounds A1541-43, exhibiting potent anti-leukemic activity, was shown to induce ERK1/2 phosphorylation. In contrast, the natural product Cedrelone, which shares structural similarities with A1541-43, functions as a potent inhibitor of ERK1/2. We provided evidence that A1541-43 and Cedrelone specifically target ERK1/2, but not the upstream MAPK/ERK pathway. Computational docking analysis predicts that compounds A1541-43 bind a region in ERK1/2 that is distinct from that to which Cedrelone and EQW bind. Interestingly, both A1541-43, which act as ERK1/2 agonists, and Cedrelone, which inhibit these kinases, exerted strong anti-proliferative activity against multiple leukemic cell lines, and induced robust apoptosis as well as erythroid and megakaryocytic differentiation in erythroleukemic cell lines. These compounds also suppressed tumor progression in a mouse model of erythroleukemia. CONCLUSIONS:This study identifies for the first time activators of ERK1/2 with therapeutic potential for the treatment of cancers driven by dysregulation of the MAPK/ERK pathway and possibly for other disorders.

Dataset Information

Identfication of Potent LXR?-Selective Agonists without LXR? Activation by In Silico Approaches.

Publications

Identfication of Potent LXRβ-Selective Agonists without LXRα Activation by In Silico Approaches.

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