作者: Snoussi, Mejdi ; Saxena, Juhi ; Jahan, Sadaf ; Badraoui, Riadh ; Siddiqui, Maqsood Ahmed ; Kumar, Vikash ; Alshahrani, Mohammed Merae ; Al Awadh, Ahmed Abdullah ; Abdelgadir, Abdelmushin ; Hamadou, Walid Sabri ; Siddiqui, Arif Jamal ; Adnan, Mohd

Very long-chain fatty acids (VLCFAs) play a direct role in the development of a neurological disorder, X-linked adrenoleukodystrophy (X-ALD). Since ELOVL1 catalyzes the rate-limiting step of the synthesis of VLCFAs, it has emerged as an attractive target for the treatment of X-ALD. Recently two potent inhibitors, compound 22 (C22) and compound 27 (C27) have been reported to specifically inhibit human ELOVL1 but their structural basis of inhibition has not been explored. In the present study, we have used a homology model of human ELOVL1 to deduce the binding site and binding modes of C22 and C27. We have employed computational approaches to characterize the binding of C22 and C27. Initially, binding of hexacosanoyl-CoA (C26:0-CoA) to ELOVL1 was modelled and further validated by molecular dynamics (MD) simulation. We observed that the fatty acid tail of C26: CoA protrudes from a unique opening located at the occluded end of ELOVL1. Structural comparison of ELOVL1 with the crystal structure of ELOVL7 revealed that the unique opening was not present in human ELOVL7. Combined blind and focused molecular docking approaches revealed that C22 and C27 exhibit favourable binding in the same unique opening. Further, MD simulations and free binding energy calculations confirmed that C22 and C27 maintain the favourable binding in the unique opening of ELOVL1. Overall, our findings suggest that selective human ELOVL1 inhibitors block the binding of long tails of VLCFAs near the occluded end of ELOVL1. Present study will be helpful in the discovery and design of novel, selective and potent inhibitors of human ELOVL1.

2022-03-21·Nucleic Acids Research

Small molecule targeting CELF1 RNA-binding activity to control HSC activation and liver fibrosis

Article

作者: Li, Fulong ; Luo, Xiaomin ; Chen, Jiayu ; Xu, Yizhu ; Ye, Yan ; Wu, Xingxin ; Xu, Qiang ; Sun, Xueqing ; Tang, Bingjie ; Tan, Yang ; Wang, Tianyi ; Xu, Shuaiqi ; Lu, Dong ; Diao, Xu

AbstractCUGBP Elav-like family member 1 (CELF1), an RNA-binding protein (RBP), plays important roles in the pathogenesis of diseases such as myotonic dystrophy, liver fibrosis and cancers. However, targeting CELF1 is still a challenge, as RBPs are considered largely undruggable. Here, we discovered that compound 27 disrupted CELF1-RNA binding via structure-based virtual screening and biochemical assays. Compound 27 binds directly to CELF1 and competes with RNA for binding to CELF1. Compound 27 promotes IFN-γ secretion and suppresses TGF-β1-induced hepatic stellate cell (HSC) activation by inhibiting CELF1-mediated IFN-γ mRNA decay. In vivo, compound 27 attenuates CCl4-induced murine liver fibrosis. Furthermore, the structure-activity relationship analysis was performed and compound 841, a derivative of compound 27, was identified as a selective CELF1 inhibitor. In conclusion, targeting CELF1 RNA-binding activity with small molecules was achieved, which provides a novel strategy for treating liver fibrosis and other CELF1-mediated diseases.

2021-12-23·Journal of Medicinal Chemistry1区 · 医学

Discovery of Novel, Orally Bioavailable Pyrimidine Ether-Based Inhibitors of ELOVL1

1区 · 医学

Article

作者: Charifson, Paul S. ; Court, John J. ; Maltais, Francois ; Bunnage, Mark E. ; Empfield, James ; Cao, Jingrong ; Engtrakul, Juntyma ; Swett, Rebecca ; Gao, Hong ; Phillips, Jonathan ; Wang, Jian ; Considine, Tony ; Li, Pan ; Waal, Nathan ; Duffy, John P. ; Cochran, John E. ; Chakilam, Ananthisrinivas ; Deng, Hongbo ; Doyle, Elizabeth ; Kesavan, Sarathy ; Clark, Michael P. ; Boucher, Christina ; O’Dowd, Hardwin ; Ronkin, Steven M. ; Jackson, Katrina L. ; Come, Jon ; Davies, Ioana ; Boyd, Michael J. ; Kemper, Raymond ; Collier, Philip N. ; Chandupatla, Kishan ; Taylor, William P. ; Magavi, Sanjay Shivayogi ; Crawford, Dan

In our efforts to identify novel small molecule inhibitors for the treatment of adrenoleukodystrophy (ALD), we conducted a high-throughput radiometric screen for inhibitors of elongation of very long chain fatty acid 1 (ELOVL1) enzyme. We developed a series of highly potent, central nervous system (CNS)-penetrant pyrimidine ether-based compounds with favorable pharmacokinetics culminating in compound 22. Compound 22 is a selective inhibitor of ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts and lymphocytes in vitro. Compound 22 reduced C26:0 lysophosphatidyl choline (LPC), a subtype of VLCFA, in the blood of ATP binding cassette transporter D1 (ABCD1) KO mice, a murine model of ALD to near wild-type levels. Compound 22 is a low-molecular-weight, potent ELOVL1 inhibitor that may serve as a useful tool for exploring therapeutic approaches to the treatment of ALD.

100 项与 ELOVL1 inhibitors(Vertex Pharmaceuticals) 相关的药物交易

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