PMID- 36270169 OWN - NLM STAT- MEDLINE DCOM- 20221117 LR - 20221117 IS - 1090-2120 (Electronic) IS - 0045-2068 (Linking) VI - 129 DP - 2022 Dec TI - Structure-based screening and biological validation of the anti-thrombotic drug-dicoumarol as a novel and potent PPARgamma-modulating ligand. PG - 106191 LID - S0045-2068(22)00597-1 [pii] LID - 10.1016/j.bioorg.2022.106191 [doi] AB - PPARgamma full agonists, thiazolidinediones (TZDs), have been known as a class of most effective drugs for the treatment of type 2 diabetes mellitus (T2DM). However, recently their therapeutic benefits have been compromised by several undesirable side effects. In this study, a host-based repurposing strategy and in combination with comprehensive biological evaluations were synergistically employed to seek for potent PPARgamma ligands, which led to the identification of an anti-thrombotic drug, dicoumarol (Dic), as the novel and safer selectively PPARgamma modulator (SPPARgammaM) with advantages over current TZD drugs. The results in vitro showed that Dic had a potent binding affinity and weakly agonistic activity for PPARgamma and its downstream key genes. Moreover, in diabetic model, it significantly reduced blood glucose without leading to the weight gain of both body and main organ tissues. Further mechanistic investigations revealed that Dic possessed such desired pharmacological properties mainly through effectively inhibiting the phosphorylation of PPARgamma-Ser273 and selectively regulating the expressions of insulin-sensitive and resistance genes. Finally, the docking studies on the analysis of the potent binding mode of Dic with PPARgamma revealed a remarkable difference on interaction region compared with other developed PPARgamma agonists, which not only gave a proof of concept for the abovementioned mechanism but also provided the molecular basis for the discrimination of Dic from other PPARgamma ligands, especially TZD drugs. Taken together, our findings suggested that Dic could serve as a new and promising candidate with good therapeutic index for treating T2DM, especially for those T2DM patients with thrombosis. CI - Copyright (c) 2022 Elsevier Inc. All rights reserved. FAU - Ma, Lei AU - Ma L AD - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. FAU - Tang, Junyuan AU - Tang J AD - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. FAU - Cai, Guihui AU - Cai G AD - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. FAU - Chen, Fangyuan AU - Chen F AD - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. FAU - Liu, Qingmei AU - Liu Q AD - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. FAU - Zhou, Zhi AU - Zhou Z AD - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. FAU - Zhang, Silin AU - Zhang S AD - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. FAU - Liu, Xiawen AU - Liu X AD - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. Electronic address: lxwgzhmu@gzhmu.edu.cn. FAU - Hou, Ning AU - Hou N AD - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. Electronic address: houning@gzhmu.edu.cn. FAU - Yi, Wei AU - Yi W AD - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. Electronic address: yiwei@gzhmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221007 PL - United States TA - Bioorg Chem JT - Bioorganic chemistry JID - 1303703 RN - 7QID3E7BG7 (Dicumarol) RN - 0 (Hypoglycemic Agents) RN - 0 (Ligands) RN - 0 (PPAR gamma) RN - 0 (Thiazolidinediones) RN - 0 (Anticoagulants) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - *Dicumarol/chemistry/pharmacology/therapeutic use MH - *Hypoglycemic Agents/chemistry MH - Ligands MH - *PPAR gamma/agonists MH - Thiazolidinediones/adverse effects/pharmacology MH - *Thrombosis/drug therapy/etiology MH - *Anticoagulants/chemistry/pharmacology OTO - NOTNLM OT - Anti-diabetic effects OT - Dicoumarol OT - Insulin sensitivity OT - SB-VHTS OT - SPPARgammaM OT - T2DM COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/10/22 06:00 MHDA- 2022/11/09 06:00 CRDT- 2022/10/21 18:26 PHST- 2022/08/04 00:00 [received] PHST- 2022/09/17 00:00 [revised] PHST- 2022/09/30 00:00 [accepted] PHST- 2022/10/22 06:00 [pubmed] PHST- 2022/11/09 06:00 [medline] PHST- 2022/10/21 18:26 [entrez] AID - S0045-2068(22)00597-1 [pii] AID - 10.1016/j.bioorg.2022.106191 [doi] PST - ppublish SO - Bioorg Chem. 2022 Dec;129:106191. doi: 10.1016/j.bioorg.2022.106191. Epub 2022 Oct 7.