To Probe Full and Partial Activation of Human Peroxisome Proliferator-Activated Receptors by Pan-Agonist Chiglitazar Using Molecular Dynamics Simulations
To Probe Full and Partial Activation of Human Peroxisome Proliferator-Activated Receptors by Pan-Agonist Chiglitazar Using Molecular Dynamics Simulations
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DOI：
10.1155/2020/5314187
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发表时间：
2020-04-01
期刊：
影响因子：
2.9
通讯作者：
Wu，Chun
中科院分区：
文献类型：
--
作者：
Sullivan，Holli-Joi;Wang，Xiaoyan;Wu，Chun
Chiglitazar是一种有前途的新一代胰岛素增敏剂，具有治疗II型糖尿病（T2 DM）的低逆转作用，并已显示出作为人过氧化物酶体增殖物激活受体（PPARs）的非选择性泛激动剂的活性（即，过氧化物酶体增殖物激活受体γ的完全激活和过氧化物酶体增殖物激活受体α和过氧化物酶体增殖物激活受体β/δ的部分激活）。然而，它与PPARs没有高分辨率的复杂结构，其详细的相互作用和激活机制仍不清楚。在这项研究中，我们将齐格列扎对接到三种实验分辨的hPPAR亚型的晶体结构中，即PPARα，PPARβ/δ和PPARγ，然后对每个系统进行3μs的分子动力学模拟。我们的MM-GBSA结合能计算显示，齐格列扎最有利于与hPPARγ（-144.6 kcal/mol）结合，其次是hPPARα（-138.0 kcal/mol）和hPPARβ（-135.9 kcal/mol），顺序与实验数据一致。通过按残基分解MM-GBSA结合能并使用二维相互作用图，确定并表征了每个复杂系统中参与齐格列扎结合的关键残基。此外，我们详细的动力学分析支持螺旋12的构象和动力学在确定不同类型的配体（例如，完全激动剂对部分激动剂）。部分激动剂不是在激动剂对拮抗剂构象的方向上完全弯曲，而是可以采用更线性的构象并且具有较低程度的柔性。我们的发现可能有助于进一步开发这种新一代药物。
Chiglitazar is a promising new‐generation insulin sensitizer with low reverse effects for the treatment of type II diabetes mellitus (T2DM) and has shown activity as a nonselective pan‐agonist to the human peroxisome proliferator‐activated receptors (PPARs) (i.e., full activation of PPARγand a partial activation of PPARαand PPARβ/δ). Yet, it has no high‐resolution complex structure with PPARs and its detailed interactions and activation mechanism remain unclear. In this study, we docked chiglitazar into three experimentally resolved crystal structures of hPPAR subtypes, PPARα, PPARβ/δ, and PPARγ, followed by 3μs molecular dynamics simulations for each system. Our MM‐GBSA binding energy calculation revealed that chiglitazar most favorably bound to hPPARγ(‐144.6 kcal/mol), followed by hPPARα(‐138.0 kcal/mol) and hPPARβ(‐135.9 kcal/mol), and the order is consistent with the experimental data. Through the decomposition of the MM‐GBSA binding energy by residue and the use of two‐dimensional interaction diagrams, key residues involved in the binding of chiglitazar were identified and characterized for each complex system. Additionally, our detailed dynamics analyses support that the conformation and dynamics of helix 12 play a critical role in determining the activities of the different types of ligands (e.g., full agonist vs. partial agonist). Rather than being bent fully in the direction of the agonist versus antagonist conformation, a partial agonist can adopt a more linear conformation and have a lower degree of flexibility. Our finding may aid in further development of this new generation of medication.