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Repurposing FDA-approved drugs as NLRP3 inhibitors against inflammatory diseases: machine learning and molecular
Vipul Agarwal1, Rajesh Haldhar2, Abdurahman Hajinur Hirad3
1Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India.
Abstract:
Activation of NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) has been associated with multiple chronic pathologies, including diabetes, atherosclerosis, and rheumatoid arthritis. Moreover, histone deacetylases (HDACs), specifically HDAC6 is required for the NLRP3 inflammasome to assemble and activate. Thus, NLRP3 serves as an attractive target for the development of novel therapeutic approaches. Several companies are now attempting to develop specific modulators of the NLRP3 inflammasome, but only a handful of small molecules of NLRP3 inflammasome inhibitors, such as MCC950 and Tranilast, are currently available for clinical use. However, their use is limited due to severe side effects and short half-lives. Thus, the repurposing of FDA-approved drugs with NLRP3 inhibitory activity is needed. The present study was aimed at repurposing preexisting drugs that might act as safe and effective NLRP3 inhibitors. A library of 2,697 FDA-approved drugs was screened for binding with NLRP3 (PDB: 7ALV) using Glide (Schrödinger). The top seven FDA-approved drugs with potential binding affinities were selected based on docking scores and subjected to ADMET profiling using pkCSM and SwissADME. The binding of the ADMET-favorable FDA-approved drugs to NLRP3 was validated using MMGBSA (Prime) and Molecular Dynamics (Desmond) in the Schrödinger suite. ADMET profiling revealed that of the seven best docking drugs, empagliflozin and citicoline had good drug-likeness properties. Moreover, MMGBSA analysis and molecular dynamics demonstrated that empagliflozin and citicoline exhibited stable ligand-NLRP3 interactions in the presence of solvents. This study sheds light on the ability of various FDA-approved drugs to act as NLRP3 inhibitors.
Insights
This study screened FDA-approved drugs to find new NLRP3 inflammasome inhibitors. Empagliflozin and citicoline showed potential as safe and effective NLRP3 inhibitors for treating chronic diseases.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- NLRP3 inflammasome activation is linked to chronic diseases like diabetes and arthritis.
- HDAC6 is crucial for NLRP3 inflammasome assembly and activation.
- Existing NLRP3 inhibitors have limitations, necessitating the search for safer alternatives.
Purpose of the Study:
- To repurpose FDA-approved drugs as novel NLRP3 inflammasome inhibitors.
- To identify safe and effective NLRP3 inhibitors through drug screening and validation.
Main Methods:
- Screened 2,697 FDA-approved drugs for NLRP3 binding using Glide docking.
- Selected top candidates for ADMET profiling (pkCSM, SwissADME).
- Validated binding affinity and stability with MMGBSA and molecular dynamics simulations.
Main Results:
- Empagliflozin and citicoline demonstrated favorable drug-likeness properties.
- These drugs exhibited stable interactions with NLRP3 in molecular dynamics simulations.
- Identified potential NLRP3 inhibitory activity in existing FDA-approved medications.
Conclusions:
- Empagliflozin and citicoline are promising candidates for NLRP3 inflammasome inhibition.
- Drug repurposing offers a viable strategy for developing novel therapeutics for NLRP3-associated pathologies.
- This research expands the therapeutic potential of existing drugs for chronic inflammatory conditions.
