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

Authors :
Shu, Yuanyuan
Yue, Jianda
Li, Yaqi
Yin, Yekui
Wang, Jiaxu
Li, Tingting
He, Xiao
Liang, Songping
Zhang, Gaihua
Liu, Zhonghua
Wang, Ying
Source :
Journal of Computer-Aided Molecular Design. 8/10/2024, Vol. 38 Issue 1, p1-18. 18p.
Publication Year :
2024

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
0920654X
Volume :
38
Issue :
1
Database :
Academic Search Index
Journal :
Journal of Computer-Aided Molecular Design
Publication Type :
Academic Journal
Accession number :
178955134
Full Text :
https://doi.org/10.1007/s10822-024-00568-y