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<p>Guanosine monophosphate synthetase (GMPS) catalyzes the ATP-dependent conversion of xanthosine monophosphate (XMP) to guanosine monophosphate (GMP), a key step in de novo purine biosynthesis. Dysregulation of GMPS expression has been implicated in multiple cancers, underscoring its potential as a therapeutic target. Here, we identified a novel small molecule GMPS inhibitor, G18, through large-scale virtual screening of 1.27&#xa0;million compounds. Biochemical validation using an inorganic phosphatase (IPP1)-coupled colorimetric assay demonstrated that G18 inhibits GMPS with an IC<sub>50</sub> of 73.8&#xa0;μM. Isothermal titration calorimetry (ITC) confirmed direct and thermodynamically favorable binding (Kd = 6.94&#xa0;μM). Moreover, G18 suppressed HeLa cell proliferation with an IC<sub>50</sub> of 73.3&#xa0;μM. Structural modeling and 500-ns molecular dynamics simulations revealed that G18 binds within the ATPase domain, forming stable hydrogen-bonding and hydrophobic interactions that stabilize the enzyme-inhibitor complex. Together, these results identify G18 as a promising lead compound for GMPS-targeted anticancer drug discovery and provide structural insights for further optimization.</p>

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Discovery of a small-molecule inhibitor targeting human GMP synthetase

  • 期刊论文

  • 发表日期：

    2025年12月19日

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  • Zhiyan Wang,
  • Rajamanikandan Sundarraj,
  • Boao Mao,
  • Jun-An Ma,
  • Kunrong Mei,
  • Zhiguang Yuchi

摘要

Guanosine monophosphate synthetase (GMPS) catalyzes the ATP-dependent conversion of xanthosine monophosphate (XMP) to guanosine monophosphate (GMP), a key step in de novo purine biosynthesis. Dysregulation of GMPS expression has been implicated in multiple cancers, underscoring its potential as a therapeutic target. Here, we identified a novel small molecule GMPS inhibitor, G18, through large-scale virtual screening of 1.27 million compounds. Biochemical validation using an inorganic phosphatase (IPP1)-coupled colorimetric assay demonstrated that G18 inhibits GMPS with an IC50 of 73.8 μM. Isothermal titration calorimetry (ITC) confirmed direct and thermodynamically favorable binding (Kd = 6.94 μM). Moreover, G18 suppressed HeLa cell proliferation with an IC50 of 73.3 μM. Structural modeling and 500-ns molecular dynamics simulations revealed that G18 binds within the ATPase domain, forming stable hydrogen-bonding and hydrophobic interactions that stabilize the enzyme-inhibitor complex. Together, these results identify G18 as a promising lead compound for GMPS-targeted anticancer drug discovery and provide structural insights for further optimization.