Characterization of Competitive Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase.
Characterization of Competitive Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase.
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DOI：
10.1002/cbic.202100704
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发表时间：
2022-04-05
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恶性疟原虫cgmp依赖性蛋白激酶（PfPKG）是一种诱人的抗疟疾药物靶点。需要新的化学型，因为现有的抑制剂存在安全问题，可能会阻碍进一步的发展。这项工作证明了基于异恶唑的化合物是有效的ATP竞争性PfPKG抑制剂，并在该系列中揭示了一种新的类似物。异恶唑3和5的Ki值与已知标准4-[2-（4-氟苯基）-5-（1-甲基哌啶-4-基）- 1h吡咯-3-基]吡啶相当。它们对PfPKG的选择性也优于人类同源基因和看门人突变体T618Q PfPKG，后者模仿了人类同源基因较难接近的结合位点。预测人类同源物更大的结合位点体积可以解释恶性疟原虫酶抑制剂的选择性。抗击疟疾需要具有新型作用机制的药物。基于异恶唑的化合物被发现是恶性疟原虫cgmp依赖性蛋白激酶的有效的、选择性的和atp竞争性的抑制剂。
P. falciparum cGMP-dependent protein kinase (PfPKG) is an enticing anti-malarial drug target. Novel chemotypes are needed because existing inhibitors have safety issues that may prevent further development. This work demonstrates isoxazole-based compounds are potent ATP competitive inhibitors of PfPKG and discloses a new analog in this series. Isoxazoles 3 and 5 had Ki values that are comparable to a known standard, 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H pyrrol-3-yl] pyridine. They also exhibited excellent selectivity for PfPKG over the human ortholog and the gatekeeper mutant T618Q PfPKG, which mimics the less accessible binding site of the human ortholog. The human ortholog’s larger binding site volume was predicted to explain the selectivity of the inhibitors for the P. falciparum enzyme. Drugs with novel mechanisms of action are needed to combat malaria. Isoxazole-based compounds were found to be potent, selective and ATP-competitive inhibitors of P. falciparum cGMP-dependent protein kinase.
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影响因子：
--
作者：
Donald, RGK;Allocco, J;Liberator, PA
通讯作者：
Liberator, PA
影响因子：
1.5
作者：
Diaz, CA;Allocco, J;Liberator, PA
通讯作者：
Liberator, PA
影响因子：
--
作者：
Taylor, Helen M.;McRobert, Louisa;Baker, David A.
通讯作者：
Baker, David A.
影响因子：
16.6
作者：
Baker DA;Stewart LB;Large JM;Bowyer PW;Ansell KH;Jiménez-Díaz MB;El Bakkouri M;Birchall K;Dechering KJ;Bouloc NS;Coombs PJ;Whalley D;Harding DJ;Smiljanic-Hurley E;Wheldon MC;Walker EM;Dessens JT;Lafuente MJ;Sanz LM;Gamo FJ;Ferrer SB;Hui R;Bousema T;Angulo-Barturén I;Merritt AT;Croft SL;Gutteridge WE;Kettleborough CA;Osborne SA
通讯作者：
Osborne SA
影响因子：
2.7
作者：
Biftu, T;Feng, D;Wyvratt, M
通讯作者：
Wyvratt, M