Two agents from natural sources, citroflavonoids naringin and naringenin, can target enzymes in pathogenic yeasts responsible for hospital infections and crop failure. The aim of this study was to examine the molecular recognition site for naringin and naringenin on the HMGR and TOPOII enzymes of eleven Candida species and one phytopathogen, U. maydis, and evaluate yeast susceptibility to these flavonoids. The HMGR and TOPOII enzymes were analyzed in silico. The alignment of the two enzymes in the twelve pathogenic organisms with the corresponding enzyme of Homo sapiens revealed highly conserved amino acid sequences. Modeling studies of the enzymes indicated highly conserved structures. According to molecular docking simulations, both citroflavonoids recognized the amino acid residues of the active site of the enzymes. Binding energy values were higher for naringin (−10.75 and −9.38 kcal/mol, respectively) than simvastatin on HMGR (−9.9) and curcumin on TOPOII (−8.37). The appraisal of twenty-nine virtual mutations provided evidence of probable mechanisms of resistance (high binding energy) or susceptibility (low energy) to the drugs and emphasized the role of key residues. An in vitro susceptibility evaluation of the twelve yeasts demonstrated that the two flavonoids have similar or better MIC values than those reported for the reference compounds, obtaining the lowest with Candida dubliniensis (2.5 µg/ml) and U. maydis (5 µg/ml). Based on the present findings, naringin and naringenin could possibly be effective for treating diseases caused by pathogenic yeasts of the Candida species and U. maydis, presumably by inhibition of their HMGR and TOPOII enzymes.

来自天然来源的两种物质，柠檬黄酮类柚皮苷和柚皮素，可以靶向导致医院感染和作物歉收的致病性酵母中的酶。本研究的目的是检查 11 种念珠菌属和一种植物病原体U. maydis的 HMGR 和 TOPOII 酶上柚皮苷和柚皮素的分子识别位点，并评估酵母对这些类黄酮的敏感性。在计算机上分析了 HMGR 和 TOPOII 酶。十二种致病生物中的两种酶与智人对应酶的比对揭示了高度保守的氨基酸序列。酶的建模研究表明高度保守的结构。根据分子对接模拟，两种柠檬黄酮都能识别酶活性位点的氨基酸残基。柚皮苷的结合能值（分别为 -10.75 和 -9.38 kcal/mol）高于 HMGR 上的辛伐他汀 (-9.9) 和 TOPOII 上的姜黄素 (-8.37)。对 29 个虚拟突变的评估提供了药物耐药性（高结合能）或易感性（低能量）的可能机制的证据，并强调了关键残基的作用。对 12 种酵母的体外敏感性评估表明，这两种类黄酮的 MIC 值与参考化合物的 MIC 值相似或更好，获得最低的都柏林念珠菌(2.5 µg/ml) 和美国玉米(5 µg/ml)。根据目前的研究结果，柚皮苷和柚皮素可能对治疗由念珠菌属和玉米霉菌的致病性酵母菌引起的疾病有效，可能是通过抑制它们的 HMGR 和 TOPOII 酶。