Programa de Pós-graduação em biotecnologia da, Universidade Estadual de Feira de Santana, Feira de Santana, Brazil.
Faculdade de Farmácia da, Universidade Federal da Bahia, Salvador, Brazil.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):1217-1229. doi: 10.1080/14756366.2021.1931165.
The thiazolidinone ring is found in compounds that have widespan biology activity and there is mechanism-based evidence that compounds bearing this moiety inhibit PhzS (PzhS), a key enzyme in the biosynthesis of the virulence factor named pyocyanin. Ten novel thiazolidinone derivatives were synthesised and screened against PhzS, using two orthogonal assays. The biological results provided by these and 28 other compounds, whose synthesis had been described, suggest that the dihydroquinazoline ring, found in the previous hit (- Kd = 18 µM and LE = 0.20), is not required for PzhS inhibition, but unsubstituted nitrogen at the thiazolidinone ring is. The molecular simplification approach, pursued in this work, afforded an optimised lead compound (- 5-(2,4-dimethoxyphenyl)thiazolidine-2,4-dione) with 10-fold improvement in affinity (Kd= 1.68 µM) and more than 100% increase in LE (0.45), which follows the same inhibition mode as the original hit compound (competitive to NADH).Executive summaryPhzS is a key enzyme in the pyocyanin biosynthesis pathway in Orthogonal assays (TSA and FITC) show that fragment-like thiazolidinedione derivatives bind to PhzS with one-digit micromolar affinity.Fragment-like thiazolidinedione derivatives bind to the cofactor (NADH) binding site in PhzS.The molecular simplification optimised the ligand efficiency and affinity of the lead compound.
噻唑烷酮环存在于具有广泛生物学活性的化合物中，有机制证据表明，含有该部分的化合物抑制 PhzS（PzhS），这是一种毒力因子——绿脓菌素生物合成中的关键酶。合成了十个新的噻唑烷酮衍生物，并使用两种正交测定法对 PhzS 进行了筛选。这些生物结果以及其他 28 种化合物（其合成已被描述）提供的结果表明，先前的命中化合物（- Kd = 18 µM 和 LE = 0.20）中发现的二氢喹唑啉环对于 PzhS 抑制不是必需的，但是噻唑烷酮环上未取代的氮是必需的。在这项工作中，采用了分子简化方法，得到了优化的先导化合物（- 5-（2,4-二甲氧基苯基）噻唑烷-2,4-二酮），亲和力提高了 10 倍（Kd = 1.68 µM），LE 提高了 100%以上（0.45），这与原始命中化合物的抑制模式相同（与 NADH 竞争）。
总结
PhzS 是绿脓菌素生物合成途径中的关键酶。
正交测定法（TSA 和 FITC）表明，类似片段的噻唑烷二酮衍生物与 PhzS 以一位数字微摩尔亲和力结合。
类似片段的噻唑烷二酮衍生物与 PhzS 中的辅酶（NADH）结合位点结合。
分子简化优化了先导化合物的配体效率和亲和力。
