Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraidah 51452, Saudi Arabia.
Department of Chemistry, University of Nebraska at Omaha, Omaha, NE 68182, USA.
Biomolecules. 2022 Nov 1;12(11):1614. doi: 10.3390/biom12111614.
The peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor and controls a number of gene expressions. The ligand binding domain (LBD) of PPARγ is large and involves two binding sites: orthosteric and allosteric binding sites. Increased evidence has shown that PPARγ is an oncogene and thus the PPARγ antagonists have potential as anticancer agents. In this paper, we use Glide Dock approach to determine which binding site, orthosteric or allosteric, would be a preferred pocket for PPARγ antagonist binding, though antidiabetic drugs such as thiazolidinediones (TZDs) bind to the orthosteric site. The Glide Dock results show that the binding of PPARγ antagonists at the allosteric site yielded results that were much closer to the experimental data than at the orthosteric site. The PPARγ antagonists seem to selectively bind to residues Lys265, Ser342 and Arg288 at the allosteric binding site, whereas PPARγ agonists would selectively bind to residues Leu228, Phe363, and His449, though Phe282 and Lys367 may also play a role for agonist binding at the orthosteric binding pocket. This finding will provide new perspectives in the design and optimization of selective and potent PPARγ antagonists or agonists.
过氧化物酶体增殖物激活受体 γ（PPARγ）是一种核受体，可控制多种基因表达。PPARγ 的配体结合域（LBD）较大，涉及两个结合位点：正位和变构结合位点。越来越多的证据表明，PPARγ 是一种癌基因，因此 PPARγ 拮抗剂具有作为抗癌药物的潜力。在本文中，我们使用 Glide Dock 方法来确定哪个结合位点（正位或变构）将是 PPARγ 拮抗剂结合的首选口袋，尽管抗糖尿病药物如噻唑烷二酮（TZDs）结合到正位。Glide Dock 的结果表明，PPARγ 拮抗剂在变构结合位点的结合产生的结果比在正位结合位点更接近实验数据。PPARγ 拮抗剂似乎选择性地结合到变构结合位点的残基 Lys265、Ser342 和 Arg288，而 PPARγ 激动剂则选择性地结合到残基 Leu228、Phe363 和 His449，尽管 Phe282 和 Lys367 也可能在正位结合口袋中发挥激动剂结合的作用。这一发现将为设计和优化选择性和有效的 PPARγ 拮抗剂或激动剂提供新的视角。
