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<p>Lactate dehydrogenase A (LDHA) plays a crucial role in aerobic glycolysis, supporting cancer cell survival. We screened 10 angiotensin II receptor blockers for LDHA inhibition and identified telmisartan as the top candidate based on docking scores. Unlike other drugs, telmisartan binds to the NADH cofactor site, suggesting competitive inhibition. Molecular dynamics simulations and MM-PBSA binding energy calculations confirmed stable interactions with key LDHA residues. Principal component analysis (PCA) and free energy landscape (FEL) analyses assessed complex stability. Following the computational studies, in-vitro enzyme kinetics assays demonstrated that telmisartan competitively inhibits LDHA by binding at the NADH site, as evidenced by Lineweaver–Burk plots. The calculated inhibition constant (Ki) and half-maximal inhibitory concentration (IC50) were 0.23 mM and 0.972 mM, respectively, supporting the computational findings. These results highlight telmisartan’s potential as a repurposable anticancer agent. However, as NADH serves as a common cofactor for several metabolic enzymes, potential off-target effects should be carefully evaluated in future studies.</p>

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Identification of telmisartan’s potential as NADH competitive lactate dehydrogenase A inhibitor unlocks its possibility for drug repurposing in cancer therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月27日

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  • Sanjay Kumar Paul,
  • Abdelmadjid Guendouzi,
  • Sutithi Dey,
  • Abdelkrim Guendouzi,
  • Rajen Haldar

摘要

Lactate dehydrogenase A (LDHA) plays a crucial role in aerobic glycolysis, supporting cancer cell survival. We screened 10 angiotensin II receptor blockers for LDHA inhibition and identified telmisartan as the top candidate based on docking scores. Unlike other drugs, telmisartan binds to the NADH cofactor site, suggesting competitive inhibition. Molecular dynamics simulations and MM-PBSA binding energy calculations confirmed stable interactions with key LDHA residues. Principal component analysis (PCA) and free energy landscape (FEL) analyses assessed complex stability. Following the computational studies, in-vitro enzyme kinetics assays demonstrated that telmisartan competitively inhibits LDHA by binding at the NADH site, as evidenced by Lineweaver–Burk plots. The calculated inhibition constant (Ki) and half-maximal inhibitory concentration (IC50) were 0.23 mM and 0.972 mM, respectively, supporting the computational findings. These results highlight telmisartan’s potential as a repurposable anticancer agent. However, as NADH serves as a common cofactor for several metabolic enzymes, potential off-target effects should be carefully evaluated in future studies.