Elucidation of furanone as ergosterol pathway inhibitor in <i>Cryptococcus neoformans</i>

In the era of antiretroviral therapy, the prevalence of Cryptococcal infection among HIV patients in developed countries has decreased considerably. However, <i>C. neoformans</i> ranks top among the critical priority pathogen that affects a wide range of immunocompromised individuals. The threat of <i>C. neoformans</i> is because of its incredibly multifaceted intracellular survival capabilities. Cell membrane sterols especially ergosterol and enzymes of its biosynthetic pathway are considered fascinating drug targets because of their structural stability. In this study, the ergosterol biosynthetic enzymes were modeled and docked with furanone derivatives. Among the tested ligands Compound <b>6</b> has shown a potential interaction with Lanosterol 14 α-demethylase. This best-docked protein-ligand complex was taken further to molecular dynamics simulation. In addition, Compound <b>6</b> was synthesized and an <i>in vitro</i> study was conducted to quantify the ergosterol in Compound <b>6</b> treated cells. Altogether the computational and <i>in vitro</i> study demonstrates that Compound <b>6</b> has anticryptococcal activity by targeting the biosynthetic pathway of ergosterol. Communicated by Ramaswamy H. Sarma在抗逆转录病毒治疗时代，发达国家HIV患者的隐球菌感染患病率已大幅下降。然而，新生隐球菌（Cryptococcus neoformans）位列最高优先级致病原之首，可感染广泛的免疫功能低下人群。新生隐球菌的致病威胁源于其极具多样性的细胞内生存能力。细胞膜固醇尤其是麦角固醇（ergosterol）及其生物合成通路中的酶类，因其结构稳定性而被视为极具潜力的药物靶点。本研究中，研究人员对麦角固醇生物合成通路中的酶类进行了结构建模，并将其与呋喃酮衍生物开展分子对接实验。在所测试的配体中，6号化合物可与羊毛甾醇14α-去甲基化酶（Lanosterol 14 α-demethylase）产生潜在相互作用。该对接效果最优的蛋白-配体复合物随后被用于分子动力学模拟研究。此外，研究人员合成了6号化合物，并开展了体外（in vitro）实验以定量检测经6号化合物处理的细胞内麦角固醇含量。综合计算生物学与体外实验结果表明，6号化合物可通过靶向麦角固醇生物合成通路发挥抗隐球菌活性。本文由Ramaswamy H. Sarma转交刊发。

搜集汇总

背景与挑战

背景概述

该数据集是关于呋喃酮作为麦角甾醇途径抑制剂在新隐球菌中的研究，包含计算建模、分子对接和体外实验的补充材料。数据集通过筛选化合物6，证实其通过靶向麦角甾醇生物合成途径发挥抗隐球菌活性，适用于生物化学、微生物学和药理学领域的研究。