Discovery and Design of Novel Small Molecule GSK-3 Inhibitors Targeting the Substrate Binding Site

被引:17
作者
Rippin, Ido [1 ]
Khazanov, Netaly [2 ]
Ben Joseph, Shirley [1 ]
Kudinov, Tania [1 ]
Berent, Eva [1 ]
Arciniegas Ruiz, Sara Melisa [1 ]
Marciano, Daniele [3 ]
Levy, Laura [2 ]
Gruzman, Arie [2 ]
Senderowitz, Hanoch [2 ]
Eldar-Finkelman, Hagit [1 ]
机构
[1] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-6997801 Tel Aviv, Israel
[2] Bar Ilan Univ, Dept Chem, IL-5290002 Ramat Gan, Israel
[3] Israel Inst Biol Res, IL-7410001 Ness Ziona, Israel
基金
以色列科学基金会;
关键词
GSK-3; pharmacophore; virtual screening; small molecules; substrate competitive inhibitors; peptides; GLYCOGEN-SYNTHASE KINASE-3-BETA; PROTEIN-KINASE INHIBITORS; BETA-CATENIN; LYSOSOMAL ACIDIFICATION; STRUCTURAL INSIGHTS; PEPTIDE INHIBITORS; PHOSPHORYLATION; TAU; GENERATION; EXPRESSION;
D O I
10.3390/ijms21228709
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The serine/threonine kinase, GSK-3, is a promising drug discovery target for treating multiple pathological disorders. Most GSK-3 inhibitors that were developed function as ATP competitive inhibitors, with typical limitations in specificity, safety and drug-induced resistance. In contrast, substrate competitive inhibitors (SCIs), are considered highly selective, and more suitable for clinical practice. The development of SCIs has been largely neglected in the past because the ambiguous, undefined nature of the substrate-binding site makes them difficult to design. In this study, we used our previously described structural models of GSK-3 bound to SCI peptides, to design a pharmacophore model and to virtually screen the "drug-like" Zinc database (similar to 6.3 million compounds). We identified leading hits that interact with critical binding elements in the GSK-3 substrate binding site and are chemically distinct from known GSK-3 inhibitors. Accordingly, novel GSK-3 SCI compounds were designed and synthesized with IC50 values of similar to 1-4 mu M. Biological activity of the SCI compound was confirmed in cells and in primary neurons that showed increased beta-catenin levels and reduced tau phosphorylation in response to compound treatment. We have generated a new type of small molecule GSK-3 inhibitors and propose to use this strategy to further develop SCIs for other protein kinases.
引用
收藏
页码:1 / 17
页数:17
相关论文
共 50 条
[41]   In silico discovery and validation of potent small-molecule inhibitors targeting the activation function 2 site of human oestrogen receptor α [J].
Singh, Kriti ;
Munuganti, Ravi Shashi Nayana ;
Leblanc, Eric ;
Lin, Yu Lun ;
Leung, Euphemia ;
Lallous, Nada ;
Butler, Miriam ;
Cherkasov, Artem ;
Rennie, Paul S. .
BREAST CANCER RESEARCH, 2015, 17
[42]   Beyond Amyloid: A Machine Learning-Driven Approach Reveals Properties of Potent GSK-3β Inhibitors Targeting Neurofibrillary Tangles [J].
Nwadiugwu, Martin ;
Onwuekwe, Ikenna ;
Ezeanolue, Echezona ;
Deng, Hongwen .
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2024, 25 (05)
[43]   Novel oxindole/benzofuran hybrids as potential dual CDK2/GSK-3β inhibitors targeting breast cancer: design, synthesis, biological evaluation, and in silico studies [J].
Eldehna, Wagdy M. ;
Al-Rashood, Sara T. ;
Al-Warhi, Tarfah ;
Eskandrani, Razan O. ;
Alharbi, Amal ;
El Kerdawy, Ahmed M. .
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2021, 36 (01) :270-285
[44]   Discovery of small molecule entry inhibitors targeting the linoleic acid binding pocket of SARS-CoV-2 spike protein [J].
Prasad, Roshny ;
Kadam, Anil ;
Padippurackal, Vinitha Vinod ;
Pulikuttymadom Balasubramanian, Aparna ;
Kumar Chandrakumaran, Naveen ;
Suresh Rangari, Kartik ;
Dnyaneshwar Khangar, Pawan ;
Ajith, Harikrishnan ;
Natarajan, Kathiresan ;
Chandramohanadas, Rajesh ;
Nelson-Sathi, Shijulal .
CURRENT SCIENCE, 2024, 126 (09)
[45]   Discovery of novel tubulin inhibitors targeting the colchicine binding site via virtual screening, structural optimization and antitumor evaluation [J].
Liu, Wei ;
Jia, Hairui ;
Guan, Minghao ;
Cui, Minxuan ;
Lan, Zhuxuan ;
He, Youyou ;
Guo, Zhongjie ;
Jiang, Ru ;
Dong, Guoqiang ;
Wang, Shengzheng .
BIOORGANIC CHEMISTRY, 2022, 118
[46]   Docking of GSK-3 beta with novel inhibitors, a target protein involved in Alzheimer's disease [J].
Joshi, Akanksha ;
Sharma, Archit ;
Kumar, Rajesh .
BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS, 2018, 11 (02) :277-284
[47]   Homology-Based Design for Selective GSK-3 Peptide Inhibitors: Patent Applications and Type 2 Diabetes Mellitus [J].
Santos, Camila Chaves ;
Chaves, Rodrigo ;
Borges, Ana Cristina ;
de Castro, Michelle Oliveira ;
Costa-Junior, Helio Miranda .
CURRENT SIGNAL TRANSDUCTION THERAPY, 2013, 8 (02) :156-164
[48]   Discovery of novel β-carboline-1,2,3-triazole hybrids as AChE/GSK-3β dual inhibitors for Alzheimer's disease treatment [J].
Liu, Wenjie ;
Tian, Liting ;
Wu, Limeng ;
Chen, Huanhua ;
Wang, Nan ;
Liu, Xin ;
Zhao, Changhao ;
Wu, Zhongchan ;
Jiang, Xiaowen ;
Wu, Qiong ;
Xu, Zihua ;
Liu, Wenwu ;
Zhao, Qingchun .
BIOORGANIC CHEMISTRY, 2022, 129
[49]   Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction [J].
Simonetta, Kyle R. ;
Taygerly, Joshua ;
Boyle, Kathleen ;
Basham, Stephen E. ;
Padovani, Chris ;
Lou, Yan ;
Cummins, Thomas J. ;
Yung, Stephanie L. ;
von Soly, Szerenke Kiss ;
Kayser, Frank ;
Kuriyan, John ;
Rape, Michael ;
Cardozo, Mario ;
Gallop, Mark A. ;
Bence, Neil F. ;
Barsanti, Paul A. ;
Saha, Anjanabha .
NATURE COMMUNICATIONS, 2019, 10
[50]   A virtual screening framework based on the binding site selectivity for small molecule drug discovery [J].
Che, Xinhao ;
Liu, Qilei ;
Yu, Fang ;
Zhang, Lei ;
Gani, Rafiqul .
COMPUTERS & CHEMICAL ENGINEERING, 2024, 184