Andrug repurposing approach to identify HDAC1 inhibitors against glioblastoma.

in Journal of biomolecular structure & dynamics by Adarsh Gopinathan, Runali Sankhe, Ekta Rathi, Triveni Kodi, Raghavendra Upadhya, K Sreedhara Ranganath Pai, Anoop Kishore

TLDR

  • The study leverages computational drug repurposing to identify HDAC1 inhibitors for the treatment of Glioblastoma, with Panobinostat showing promising results in cytotoxicity and HDAC1 reduction.
  • This approach offers a new therapeutic avenue for Glioblastoma treatment and underscores the importance of interdisciplinary research in discovering novel treatments.

Abstract

Despite considerable improvement in therapy and diagnosis, brain tumors remain a global public health concern. Among all brain tumors, 80% are due to Glioblastoma. The average survival rate of a patient once diagnosed with glioblastoma is 15 months. Lately, the role of peptidase enzymes, especially Neprilysin, a neutral endopeptidase, is gaining attention for its role in tumor growth regulation. Neprilysin expressions are positively correlated with several tumors including GBM and reduced expression of NEP protein is associated with the pathogenesis of multiple tumors. One of the main reasons for NEP protein downregulation is the action of Histone deacetylase (HDAC) enzymes, especially HDAC1. Additionally, studies have reported that increased levels of HDAC1 are responsible for downregulating NEP gene expression. Hence, HDAC1 inhibition can be a good target to elevate NEP levels, which can be a good therapeutic approach to GBM. This study utilizes the computational drug repurposing tool, Schrodinger Maestro to identify HDAC1 inhibitors from the ZINC15 database.1379 FDA-approved drugs from the ZINC15 database were screened through molecular docking. Based on docking score and ligand-protein interaction, the top ten molecules were selected which were then subjected to binding energy calculation and molecular dynamics (MD) simulations. The three most active drugs from the MD simulations- ZINC22010649 (Panobinostat), ZINC4392649 (Tasimelteon) and ZINC1673 (Melphalan), were tested on C6 and U87 MG glioblastoma cells for cytotoxicity and HDAC1 protein levels using western blot analysis. Among the three drugs, Panobinostat exhibited potent cytotoxic action and showed a significant reduction in the HDAC1 protein levels.Communicated by Ramaswamy H. Sarma.

Overview

  • The study focuses on the role of peptidase enzymes, particularly Neprilysin, in regulating tumor growth, and its relevance to Glioblastoma.
  • The study utilizes computational drug repurposing to identify HDAC1 inhibitors from the ZINC15 database and tests their effectiveness on glioblastoma cells.
  • The primary objective is to investigate the potential therapeutic approach of HDAC1 inhibition to elevate NEP levels and treat Glioblastoma.

Comparative Analysis & Findings

  • The study identified the top ten molecules from the ZINC15 database as HDAC1 inhibitors based on docking score and ligand-protein interaction.
  • Panobinostat, Tasimelteon, and Melphalan showed the most promising results in MD simulations, with Panobinostat exhibiting potent cytotoxic action and significant reduction in HDAC1 protein levels.
  • The study found that Panobinostat had a significant impact on glioblastoma cells, reducing HDAC1 protein levels and exhibiting cytotoxic action, making it a potential therapeutic approach for Glioblastoma treatment.

Implications and Future Directions

  • The study provides a new therapeutic approach for Glioblastoma treatment by targeting HDAC1 inhibition to elevate NEP levels.
  • Further studies could examine the efficacy of Panobinostat in clinical trials and explore its potential combination with other therapies for improved outcomes.
  • The study highlights the importance of computational drug repurposing in identifying novel therapeutic agents for rare and devastating diseases like Glioblastoma.
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