Grupo de Química Medicinal do Instituto de Química de São Carlos da Universidade de São Paulo Av. Trabalhador Sancarlense, 400, 13566-590, São Carlos/SP, Brazil.
Future Med Chem. 2014 Jan;6(1):17-33. doi: 10.4155/fmc.13.185.
The enzyme gapdh, which acts in the glycolytic pathway, is seen as a potential target for pharmaceutical intervention of chagas disease.
Herein, we report the discovery of new Trypanosoma cruzi GAPDH (TcGAPDH) inhibitors from target- and ligand-based virtual screening protocols using isothermal titration calorimetry (ITC) and molecular dynamics. Molecular dynamics simulations were used to gain insight on the binding poses of newly identified inhibitors acting at the TcGAPDH substrate (G3P) site.
Nequimed125, the most potent inhibitor to act upon TcGAPDH so far, which sits on the G3P site without any contact with the co-factor (NAD(+)) site, underpins the result obtained by ITC that it is a G3P-competitive inhibitor. Molecular dynamics simulation provides biding poses of TcGAPDH inhibitors that correlate with mechanisms of inhibition observed by ITC. Overall, a new class of dihydroindole compounds that act upon TcGAPDH through a competitive mechanism of inhibition as proven by ITC measurements also kills T. cruzi.
在糖酵解途径中起作用的酶 gapdh 被视为治疗恰加斯病的药物干预的潜在靶点。
本文报告了使用等温滴定量热法（ITC）和分子动力学，从基于靶标和配体的虚拟筛选方案中发现的新型 Trypanosoma cruzi GAPDH（TcGAPDH）抑制剂。分子动力学模拟用于深入了解在 TcGAPDH 底物（G3P）结合部位起作用的新鉴定抑制剂的结合构象。
迄今为止，对 TcGAPDH 作用最强的抑制剂 Nequimed125 位于 G3P 结合部位，与辅酶（NAD（+））结合部位没有任何接触，这支持了 ITC 获得的结果，即它是一种 G3P 竞争性抑制剂。分子动力学模拟提供了 TcGAPDH 抑制剂的结合构象，与 ITC 观察到的抑制机制相关。总体而言，通过 ITC 测量证明作用于 TcGAPDH 的新型二氢吲哚化合物通过竞争性抑制机制起作用，也能杀死 T. cruzi。
