Identification of a novel PPARγ modulator with good anti-diabetic therapeutic index via structure-based screening, optimization and biological validation
PPARγ is well-known as the target receptor of TZD anti-diabetic drugs. However, recently the therapeutic benefits of these TZD drugs have been compromised by many severe side effects because of their full PPARγ agonistic action to lock the AF-2 helix. Herein, we conducted a virtual screening in the...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-10-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332222010423 |
| _version_ | 1798003167084937216 |
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| author | Fangyuan Chen Lei Ma Guihui Cai Junyuan Tang Yi Wang Qingmei Liu Xiawen Liu Ning Hou Zhi Zhou Wei Yi |
| author_facet | Fangyuan Chen Lei Ma Guihui Cai Junyuan Tang Yi Wang Qingmei Liu Xiawen Liu Ning Hou Zhi Zhou Wei Yi |
| author_sort | Fangyuan Chen |
| collection | DOAJ |
| description | PPARγ is well-known as the target receptor of TZD anti-diabetic drugs. However, recently the therapeutic benefits of these TZD drugs have been compromised by many severe side effects because of their full PPARγ agonistic action to lock the AF-2 helix. Herein, we conducted a virtual screening in the combination with structure-based design, synthesis and biological evaluation both in vitro and in vivo, leading to the identification of a potent candidate YG-C-20 as the SPPARγM with improved and safer anti-diabetic therapeutics. Mechanistically, this compound presented such desired pharmacological profiles (e.g., preferable anti-diabetic efficiencies and minimized side effects) mainly via selectively inhibiting the CDK5-mediated phosphorylation of PPARγ-Ser273 and up-regulating the expression of insulin-sensitive genes Adiponectin and Glut4, yet lacking the classical full agonism to induce the adipogenesis and the expression of key adipogenic genes including PPARγ, aP2, CD36, LPL, C/EBPα and FASN. Further validation led to the final recognition of its (R)-configured isomer as the potential conformational form. Subsequent molecular docking studies revealed a unique hydrogen-bonding network of (R)-YG-C-20 with three full PPARγ agonism-unrelated residues, especially with PPARγ-Ser273 phosphorylation-associated site Ser342, which not only gives a clear verification for our structure-based design but also provides a proof of concept for the abovementioned molecular mechanism. |
| first_indexed | 2024-04-11T12:03:36Z |
| format | Article |
| id | doaj.art-01fd8056f7d949028202def506a98745 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-11T12:03:36Z |
| publishDate | 2022-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-01fd8056f7d949028202def506a987452022-12-22T04:24:46ZengElsevierBiomedicine & Pharmacotherapy0753-33222022-10-01154113653Identification of a novel PPARγ modulator with good anti-diabetic therapeutic index via structure-based screening, optimization and biological validationFangyuan Chen0Lei Ma1Guihui Cai2Junyuan Tang3Yi Wang4Qingmei Liu5Xiawen Liu6Ning Hou7Zhi Zhou8Wei Yi9Guangzhou 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, ChinaGuangzhou 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, ChinaGuangzhou 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, ChinaGuangzhou 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, ChinaGuangzhou 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, ChinaGuangzhou 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, ChinaGuangzhou 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, ChinaGuangzhou 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; Corresponding authors at: 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.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; The Sixth Affiliated Hospital and Qingyuan People’s Hospital, Guangzhou Medical University, Qingyuan, Guangdong 511518, China; Corresponding authors at: 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.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; Corresponding authors at: 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.PPARγ is well-known as the target receptor of TZD anti-diabetic drugs. However, recently the therapeutic benefits of these TZD drugs have been compromised by many severe side effects because of their full PPARγ agonistic action to lock the AF-2 helix. Herein, we conducted a virtual screening in the combination with structure-based design, synthesis and biological evaluation both in vitro and in vivo, leading to the identification of a potent candidate YG-C-20 as the SPPARγM with improved and safer anti-diabetic therapeutics. Mechanistically, this compound presented such desired pharmacological profiles (e.g., preferable anti-diabetic efficiencies and minimized side effects) mainly via selectively inhibiting the CDK5-mediated phosphorylation of PPARγ-Ser273 and up-regulating the expression of insulin-sensitive genes Adiponectin and Glut4, yet lacking the classical full agonism to induce the adipogenesis and the expression of key adipogenic genes including PPARγ, aP2, CD36, LPL, C/EBPα and FASN. Further validation led to the final recognition of its (R)-configured isomer as the potential conformational form. Subsequent molecular docking studies revealed a unique hydrogen-bonding network of (R)-YG-C-20 with three full PPARγ agonism-unrelated residues, especially with PPARγ-Ser273 phosphorylation-associated site Ser342, which not only gives a clear verification for our structure-based design but also provides a proof of concept for the abovementioned molecular mechanism.http://www.sciencedirect.com/science/article/pii/S0753332222010423SB-VHTSSPPARγMBenzozodihydropyran derivativesAnti-diabetic effectsPPARγ-Ser273 phosphorylation |
| spellingShingle | Fangyuan Chen Lei Ma Guihui Cai Junyuan Tang Yi Wang Qingmei Liu Xiawen Liu Ning Hou Zhi Zhou Wei Yi Identification of a novel PPARγ modulator with good anti-diabetic therapeutic index via structure-based screening, optimization and biological validation Biomedicine & Pharmacotherapy SB-VHTS SPPARγM Benzozodihydropyran derivatives Anti-diabetic effects PPARγ-Ser273 phosphorylation |
| title | Identification of a novel PPARγ modulator with good anti-diabetic therapeutic index via structure-based screening, optimization and biological validation |
| title_full | Identification of a novel PPARγ modulator with good anti-diabetic therapeutic index via structure-based screening, optimization and biological validation |
| title_fullStr | Identification of a novel PPARγ modulator with good anti-diabetic therapeutic index via structure-based screening, optimization and biological validation |
| title_full_unstemmed | Identification of a novel PPARγ modulator with good anti-diabetic therapeutic index via structure-based screening, optimization and biological validation |
| title_short | Identification of a novel PPARγ modulator with good anti-diabetic therapeutic index via structure-based screening, optimization and biological validation |
| title_sort | identification of a novel pparγ modulator with good anti diabetic therapeutic index via structure based screening optimization and biological validation |
| topic | SB-VHTS SPPARγM Benzozodihydropyran derivatives Anti-diabetic effects PPARγ-Ser273 phosphorylation |
| url | http://www.sciencedirect.com/science/article/pii/S0753332222010423 |
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