Opportunistic fungi of the genus Candida are currently considered as the major causative agents of mycoses, which are characterized by an especially severe course under conditions of acquired immunodeficiency. The main target for the development of new antimycotics is the cytochrome P450 51 (CYP51) of the pathogenic fungus. The widespread distribution of Candida strains resistant to the azole class of CYP51 inhibitors point to the clear need for the screening for CYP51 inhibitors both among non-azole compounds and among clinically used drugs, which would be repositioned as antimycotics. In this study an integrated approach including bioinformatics analysis, computer molecular modeling, and a surface plasmon resonance (SPR) technology was employed to identify potential inhibitors from the non-azole group. Using in silico modeling, the binding sites for acetylsalicylic acid, ibuprofen, chlorpromazine and haloperidol (these compounds, according to the literature, showed antimycotic activity) were predicted in the active site of CYP51 from Candida albicans and Candida glabrata. The K_d values of molecular complexes of acetylsalicylic acid, ibuprofen and haloperidol with CYP51, determined by SPR analysis, ranged from 18 μM to 126 μM. It was also shown that structural derivatives of haloperidol, containing various substituents, could be positioned in the active site Candida albicans CYP51 with possible formation of coordination bonds between the hydroxyl groups of the derivatives and the heme iron atom of CYP51. Thus, the potential lead structures of non-azole compounds have been proposed; they can be used for the design of new CYP51 inhibitors of Candida fungi.

念珠菌属的机会性真菌目前被认为是真菌病的主要病原体，其特征是在获得性免疫缺陷的条件下病程特别严重。开发新型抗真菌药的主要目标是致病真菌的细胞色素 P450 51 (CYP51)。念珠菌广泛分布对唑类 CYP51 抑制剂耐药的菌株表明，明确需要在非唑类化合物和临床使用的药物中筛选 CYP51 抑制剂，这些药物将重新定位为抗真菌药。在这项研究中，采用了包括生物信息学分析、计算机分子建模和表面等离子体共振 (SPR) 技术在内的综合方法来识别来自非唑基的潜在抑制剂。使用计算机模拟，乙酰水杨酸、布洛芬、氯丙嗪和氟哌啶醇（这些化合物，根据文献，显示出抗真菌活性）的结合位点在来自白色念珠菌和光滑念珠菌的 CYP51 活性位点中进行了预测。该ķ _d通过 SPR 分析测定的乙酰水杨酸、布洛芬和氟哌啶醇与 CYP51 的分子复合物的值范围为 18 μM 至 126 μM。还表明，含有各种取代基的氟哌啶醇结构衍生物可位于白色念珠菌CYP51的活性位点，并可能在衍生物的羟基与 CYP51 的血红素铁原子之间形成配位键。因此，已经提出了非唑类化合物的潜在先导结构；它们可用于设计新的念珠菌CYP51 抑制剂。