Mottin Melina, Souza Paulo C T, Ricci Clarisse G, Skaf Munir S
Institute of Chemistry, University of Campinas-UNICAMP, P.O. Box 6154, Campinas 13082-864, SP, Brazil.
Faculty of Pharmacy, Federal University of Goias, Goiânia 74605-170, GO, Brazil.
Int J Mol Sci. 2016 Dec 22;18(1):15. doi: 10.3390/ijms18010015.
The peroxisome proliferator-activated receptor γ (PPARγ) ligands are important therapeutic drugs for the treatment of type 2 diabetes, obesity and cardiovascular diseases. In particular, partial agonists and non-agonists are interesting targets to reduce glucose levels, presenting few side effects in comparison to full agonists. In this work, we present a set of CHARMM-based parameters of a molecular mechanics force field for two PPARγ ligands, GQ16 and SR1664. GQ16 belongs to the thiazolidinedione class of drugs and it is a PPARγ partial agonist that has been shown to promote the "browning" of white adipose tissue. SR1664 is the precursor of the PPARγ non-agonist class of ligands that activates PPARγ in a non-classical manner. Here, we use quantum chemical calculations consistent with the CHARMM protocol to obtain bonded and non-bonded parameters, including partial atomic charges and effective torsion potentials for both molecules. The newly parameterized models were evaluated by examining the behavior of GQ16 and SR1664 free in water and bound to the ligand binding pocket of PPARγ using molecular dynamics simulations. The potential parameters derived here are readily transferable to a variety of pharmaceutical compounds and similar PPARγ ligands.
过氧化物酶体增殖物激活受体γ（PPARγ）配体是治疗2型糖尿病、肥胖症和心血管疾病的重要治疗药物。特别是，部分激动剂和非激动剂是降低血糖水平的有趣靶点，与完全激动剂相比副作用较少。在这项工作中，我们提出了基于CHARMM的分子力学力场的一组参数，用于两种PPARγ配体GQ16和SR1664。GQ16属于噻唑烷二酮类药物，是一种PPARγ部分激动剂，已被证明可促进白色脂肪组织的“褐变”。SR1664是PPARγ非激动剂类配体的前体，它以非经典方式激活PPARγ。在这里，我们使用与CHARMM协议一致的量子化学计算来获得键合和非键合参数，包括两个分子的部分原子电荷和有效扭转势。通过使用分子动力学模拟检查GQ16和SR1664在水中自由以及与PPARγ配体结合口袋结合时的行为，对新参数化的模型进行了评估。这里导出的势参数很容易转移到各种药物化合物和类似的PPARγ配体上。
