2. Academic Validation
  3. Development of human lactate dehydrogenase a inhibitors: high-throughput screening, molecular dynamics simulation and enzyme activity assay

Development of human lactate dehydrogenase a inhibitors: high-throughput screening, molecular dynamics simulation and enzyme activity assay

  • J Comput Aided Mol Des. 2024 Aug 10;38(1):28. doi: 10.1007/s10822-024-00568-y.
Yuanyuan Shu 1 2 3,  Jianda Yue 1 2 3,  Yaqi Li 1 2 3,  Yekui Yin 1 2 3,  Jiaxu Wang 1 2 3,  Tingting Li 1 2 3,  Xiao He 4 5,  Songping Liang 1 2 3,  Gaihua Zhang 6 7 8,  Zhonghua Liu 9 10 11,  Ying Wang 12 13 14
Affiliations

Affiliations

  • 1 The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
  • 2 Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China.
  • 3 Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha, 410081, Hunan, China.
  • 4 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Frontiers Science Center of Molecule Intelligent Syntheses, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
  • 5 New York University, East China Normal University Center for Computational Chemistry, New York University Shanghai, Shanghai, 200062, China.
  • 6 The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China. ghzhang@hunnu.edu.cn.
  • 7 Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China. ghzhang@hunnu.edu.cn.
  • 8 Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha, 410081, Hunan, China. ghzhang@hunnu.edu.cn.
  • 9 The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China. liuzh@hunnu.edu.cn.
  • 10 Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China. liuzh@hunnu.edu.cn.
  • 11 Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha, 410081, Hunan, China. liuzh@hunnu.edu.cn.
  • 12 The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China. wangyin@hunnu.edu.cn.
  • 13 Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China. wangyin@hunnu.edu.cn.
  • 14 Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha, 410081, Hunan, China. wangyin@hunnu.edu.cn.
PMID: 39123063 DOI: 10.1007/s10822-024-00568-y
Abstract

Lactate Dehydrogenase A (LDHA) is highly expressed in many tumor cells and promotes the conversion of pyruvate to lactic acid in the glucose pathway, providing energy and synthetic precursors for rapid proliferation of tumor cells. Therefore, inhibition of LDHA has become a widely concerned tumor treatment strategy. However, the research and development of highly efficient and low toxic LDHA small molecule inhibitors still faces challenges. To discover potential inhibitors against LDHA, virtual screening based on molecular docking techniques was performed from Specs database of more than 260,000 compounds and Chemdiv-smart database of more than 1,000 compounds. Through molecular dynamics (MD) simulation studies, we identified 12 potential LDHA inhibitors, all of which can stably bind to human LDHA protein and form multiple interactions with its active central residues. In order to verify the inhibitory activities of these compounds, we established an Enzyme activity assay system and measured their inhibitory effects on recombinant human LDHA. The results showed that Compound 6 could inhibit the catalytic effect of LDHA on pyruvate in a dose-dependent manner with an EC50 value of 14.54 ± 0.83 µM. Further in vitro experiments showed that Compound 6 could significantly inhibit the proliferation of various tumor cell lines such as pancreatic Cancer cells and lung Cancer cells, reduce intracellular lactic acid content and increase intracellular Reactive Oxygen Species (ROS) level. In summary, through virtual screening and in vitro validation, we found that Compound 6 is a small molecule inhibitor for LDHA, providing a good lead compound for the research and development of LDHA related targeted anti-tumor drugs.

Keywords

Anticancer drug; Cancer metabolism; Lactate dehydrogenase A; Molecular dynamics simulation.

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