2. Academic Validation
  3. Deploying the high-throughput virtual screening (HTVS) approach for the identification of new lactate dehydrogenase (LDH) inhibitors with anticancer assets

Deploying the high-throughput virtual screening (HTVS) approach for the identification of new lactate dehydrogenase (LDH) inhibitors with anticancer assets

  • Sci Rep. 2026 Jan 21;16(1):5921. doi: 10.1038/s41598-026-36385-6.
Yaxun Huang 1 2,  Sangeeta Benni 3,  Umesh Prasad Yadav 4,  M Arockia Babu 5,  Akash Verma 6,  Thakur Gurjeet Singh 7,  Nisha Bansal 8,  Yulong Zhang 9
Affiliations

Affiliations

  • 1 Department of Liver Transplantation, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
  • 2 Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope National Medical Centre, Duarte, CA, 91010, USA.
  • 3 Department of Chemical Engineering, SEMR, D Y Patil International University, Akurdi, Pune, 411044, Maharashtra, India.
  • 4 Department of Hematologic Malignancies Translational Science, City of Hope Medical Centre, Duarte, CA, 91010, USA.
  • 5 Institute of Pharmaceutical Research, GLA University, Mathura, 281406, Uttar Pradesh, India.
  • 6 Teerthanker Mahaveer College of Pharmacy, Teerthanker Mahaveer University, Moradabad, 244001, Uttar Pradesh, India.
  • 7 Centre of Research Impact and Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
  • 8 Department of Biotechnology, Graphic Era Deemed to be University, Dehradun, 248002, Uttarakhand, India.
  • 9 Department of Urology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412007, China. [email protected].
PMID: 41565942 DOI: 10.1038/s41598-026-36385-6
Abstract

The tumor cells frequently rely on glycolysis to produce adenosine 5'-triphosphate (ATP), even when sufficient oxygen is available to allow Oxidative Phosphorylation (the Warburg effect). In these malignancies, the breakdown of glucose to pyruvate, instead of reaching the mitochondria, is transformed to lactate by an enzyme called Lactate Dehydrogenase (LDH) and then expelled by the cells, further fuelling the tumour microenvironment (TME). LDH facilitates the translation of pyruvate to lactate, hence replenishing the required NAD + equivalents for the ongoing glycolysis process. Having a pivotal role in Cancer cells' prognosis and survival, and affecting the TME. To date, no inhibitors have yet been approved against the LDH. However, numerous clinical trials are ongoing, and results are yet to be awaited. Considering the existing gap, we present herein a high-throughput virtual screening (HTVS) approach to identify new compounds that effectively inhibit LDH activity. We generated the pharmacophore model based on 28 LDH enzyme inhibitors from previous literature. The model was used to screen 500,000 ligands in addition to their molecular docking and drug-likeness filtering. The analysis led to the identification of 5 hits, which were further subjected to the MD simulations. Further considering the outcome of molecular dynamics results, we selected ligands 15 and 422 to corroborate their Anticancer potential via inhibiting the LDH enzyme. The biological validation revealed that both ligands, 15 and 422, possess IC50 values of 147.34 and 206.35 nM, respectively, against LDH. The Anticancer potential analysis of DU-145 and PC-3 also established their Anticancer properties, and both compounds were found to marginally elevate oxidative stress, change mitochondrial membrane potential, and induce Apoptosis in DU-145 cells.

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