Development of human lactate dehydrogenase a inhibitors: high-throughput screening, molecular dynamics simulation and enzyme activity assay.
Anticancer drug
Cancer metabolism
Lactate dehydrogenase A
Molecular dynamics simulation
Journal
Journal of computer-aided molecular design
ISSN: 1573-4951
Titre abrégé: J Comput Aided Mol Des
Pays: Netherlands
ID NLM: 8710425
Informations de publication
Date de publication:
10 Aug 2024
10 Aug 2024
Historique:
received:
04
03
2024
accepted:
24
07
2024
medline:
10
8
2024
pubmed:
10
8
2024
entrez:
9
8
2024
Statut:
epublish
Résumé
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 EC
Identifiants
pubmed: 39123063
doi: 10.1007/s10822-024-00568-y
pii: 10.1007/s10822-024-00568-y
doi:
Substances chimiques
Enzyme Inhibitors
0
Antineoplastic Agents
0
L-Lactate Dehydrogenase
EC 1.1.1.27
LDHA protein, human
EC 1.1.1.27
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
28Subventions
Organisme : National Natural Science Foundation of China
ID : 21903024, 32071262, 32171271, 32271329
Organisme : National Natural Science Foundation of China
ID : 21903024, 32071262, 32171271, 32271329
Organisme : National Natural Science Foundation of China
ID : 21903024, 32071262, 32171271, 32271329
Organisme : Science and Technology Program of Hunan Province
ID : 2020RC4023
Organisme : Scientific Research Program of FuRong Laboratory
ID : 2023SK2096
Organisme : Natural Science Foundation of Hunan Procinve
ID : 2024JJ2042
Organisme : Scientific research project of Department of Education of Hunan Province
ID : 23A0084
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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