The enzymes responsible for biotin biosynthesis in mycobacteria have been considered as potential drug targets owing to the important role in infection and cell survival that the biotin synthetic pathway plays in Mycobacterium tuberculosis. Among the enzymes that comprise mycobacterium biotin biosynthesis systems, 7,8-diaminopelargonic acid synthase (DAPAS) plays an essential role during the stationary phase in bacterial growth. In this study, compounds that inhibit mycobacterial DAPAS were screened in the virtual chemical library using an in silico structure-based drug screening (SBDS) technique, and the antimycobacterial activity of the selected compounds was validated experimentally. The DOCK-GOLD programs utilized by in silico SBDS facilitated the identification of a compound, referred to as KMD6, with potent inhibitory effects on the growth of model mycobacteria (M. smegmatis). The subsequent compound search, which was based on the structural features of KMD6, resulted in identification of three additional active compounds, designated as KMDs3, KMDs9 and KMDs10. The inhibitory effect of these compounds was comparable to that of isoniazid, which is a first-line antituberculosis drug. The high antimycobacterial activity of KMD6, KMDs9 and KMDs10 was maintained on the experiment with M. tuberculosis. Of the active compounds identified, KMDs9 would be a promising pharmacophore, owing to its long-term antimycobacterial effect and lack of cytotoxicity.

中文翻译：

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通过基于计算机模拟结构的药物筛选，鉴定出一类具有抗结核活性的新型小化合物。

由于生物素合成途径在结核分枝杆菌中的感染和细胞存活中起着重要作用，因此在分枝杆菌中负责生物素生物合成的酶已被认为是潜在的药物靶标。在组成分枝杆菌生物素生物合成系统的酶中，7,8-二氨基壬酸合酶（DAPAS）在细菌生长的固定阶段起着至关重要的作用。在这项研究中，使用基于计算机模拟结构的药物筛选（SBDS）技术在虚拟化学库中筛选了抑制分枝杆菌DAPAS的化合物，并通过实验验证了所选化合物的抗分枝杆菌活性。计算机SBDS使用的DOCK-GOLD程序有助于鉴定称为KMD6的化合物，对模型分枝杆菌（耻垢分枝杆菌）的生长具有有效的抑制作用。随后的化合物搜索基于KMD6的结构特征，导致鉴定了另外三种活性化合物，分别称为KMDs3，KMDs9和KMDs10。这些化合物的抑制作用与一线抗结核药异烟肼相当。在结核分枝杆菌的实验中，保持了KMD6，KMDs9和KMDs10的高抗分枝杆菌活性。在已鉴定的活性化合物中，由于其长期的抗分枝杆菌作用和缺乏细胞毒性，KMDs9将是一种有前途的药效团。指定为KMDs3，KMDs9和KMDs10。这些化合物的抑制作用与一线抗结核药异烟肼相当。在结核分枝杆菌的实验中，保持了KMD6，KMDs9和KMDs10的高抗分枝杆菌活性。在已鉴定的活性化合物中，由于其长期的抗分枝杆菌作用和缺乏细胞毒性，KMDs9将是一种有前途的药效团。指定为KMDs3，KMDs9和KMDs10。这些化合物的抑制作用与一线抗结核药异烟肼相当。在结核分枝杆菌的实验中，保持了KMD6，KMDs9和KMDs10的高抗分枝杆菌活性。在已鉴定的活性化合物中，由于其长期的抗分枝杆菌作用和缺乏细胞毒性，KMDs9将是一种有前途的药效团。