Glucokinase (GLK) and Hexokinase (HK) have been characterized as essential targets in Trypanosoma cruzi ( Tc )-mediated infection. A recent study reported the propensity of the concomitant inhibition of Tc GLK and Tc HK by compounds GLK2-003 and GLK2-004, thereby presenting an efficient approach in Chagas disease treatment. We investigated this possibility using atomic and molecular scaling methods. Sequence alignment of Tc GLK and Tc HK revealed that both proteins shared approximately 33.3% homology in their glucose/inhibitor binding sites. The total binding free energies of GLK2-003 and GLK2-004 were favorable in both proteins. PRO92 and THR185 were pivotal to the binding and stabilization of the ligands in Tc GLK, likewise their conserved counterparts, PRO163 and THR237 in Tc HK. Both compounds also induced a similar pattern of perturbations in both Tc GLK and Tc HK secondary structure. Findings from this study therefore provide insights into the underlying mechanisms of dual inhibition exhibited by the compounds. These results can pave way to discover and optimize novel dual Tc inhibitors with favorable pharmacokinetics properties eventuating in the mitigation of Chagas disease.

中文翻译：

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对锥虫病治疗中克氏锥虫葡萄糖激酶和己糖激酶双重抑制作用的机制探讨——一块石头杀死两只鸟？

葡萄糖激酶 (GLK) 和己糖激酶 (HK) 已被表征为克氏锥虫 (Tc) 介导的感染中的重要靶标。最近的一项研究报告了化合物 GLK2-003 和 GLK2-004 同时抑制 Tc GLK 和 Tc HK 的倾向，从而提供了一种治疗恰加斯病的有效方法。我们使用原子和分子缩放方法研究了这种可能性。Tc GLK 和 Tc HK 的序列比对表明，这两种蛋白质在其葡萄糖/抑制剂结合位点上具有大约 33.3% 的同源性。GLK2-003 和 GLK2-004 的总结合自由能在两种蛋白质中都是有利的。PRO92 和 THR185 对 Tc GLK 中配体的结合和稳定至关重要，同样它们的保守对应物 PRO163 和 THR237 在 Tc HK 中也是如此。两种化合物还在 Tc GLK 和 Tc HK 二级结构中诱导了类似的扰动模式。因此，这项研究的结果提供了对化合物表现出的双重抑制的潜在机制的见解。这些结果可以为发现和优化具有有利药代动力学特性的新型双 Tc 抑制剂铺平道路，最终减轻恰加斯病。