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首页> 外文期刊>BMC Genomics >Blocking Protein kinase C signaling pathway: mechanistic insights into the anti-leishmanial activity of prospective herbal drugs from Withania somnifera
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Blocking Protein kinase C signaling pathway: mechanistic insights into the anti-leishmanial activity of prospective herbal drugs from Withania somnifera

机译：阻断蛋白激酶C信号传导途径：茄子枯萎病抗草药活性的机制性见解

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Background Leishmaniasis is caused by several species of leishmania protozoan and is one of the major vector-born diseases after malaria and sleeping sickness. Toxicity of available drugs and drug resistance development by protozoa in recent years has made Leishmaniasis cure difficult and challenging. This urges the need to discover new antileishmanial-drug targets and antileishmanial-drug development. Results Tertiary structure of leishmanial protein kinase C was predicted and found stable with a RMSD of 5.8? during MD simulations. Natural compound withaferin A inhibited the predicted protein at its active site with -28.47 kcal/mol binding free energy. Withanone was also found to inhibit LPKC with good binding affinity of -22.57 kcal/mol. Both withaferin A and withanone were found stable within the binding pocket of predicted protein when MD simulations of ligand-bound protein complexes were carried out to examine the consistency of interactions between the two. Conclusions Leishmanial protein kinase C (LPKC) has been identified as a potential target to develop drugs against Leishmaniasis. We modelled and refined the tertiary structure of LPKC using computational methods such as homology modelling and molecular dynamics simulations. This structure of LPKC was used to reveal mode of inhibition of two previous experimentally reported natural compounds from Withania somnifera - withaferin A and withanone.
机译：背景技术利什曼病是由几种利什曼原虫引起的，是疟疾和昏睡病之后主要的媒介传播疾病之一。近年来，可用药物的毒性和原生动物对药物的耐药性使利什曼病的治疗变得困难而具有挑战性。因此，迫切需要发现新的抗疟药目标和抗疟药的发展。结果预测了利什曼蛋白激酶C的三级结构，并发现其稳定，RMSD为5.8？在MD模拟中。具有干扰素A的天然化合物以-28.47 kcal / mol的结合自由能在其活性位点抑制了预测的蛋白质。还发现Withanone以-22.57 kcal / mol的良好结合亲和力抑制LPKC。当进行配体结合蛋白复合物的MD模拟以检查两者之间相互作用的一致性时，在预测蛋白的结合口袋中发现atferin A和withanone都是稳定的。结论利什曼蛋白激酶C（LPKC）被确定为开发抗利什曼病药物的潜在靶标。我们使用同源建模和分子动力学模拟等计算方法对LPKC的三级结构进行了建模和完善。 LPKC的这种结构被用来揭示抑制来自Withania somnifera的两种先前实验报道的天然化合物的抑制方式——withaferin A和withanone。

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