Structural insight into TNF-α inhibitors through combining pharmacophore-based virtual screening and molecular...

Area of Science:

• Computational chemistry
• Drug discovery
• Immunology

Background:

• Tumor Necrosis Factor-alpha (TNF-α) is a critical cytokine in immune responses, inflammation, and cancer.
• Existing TNF-α inhibitors (e.g., antibodies) have limitations, necessitating the development of small molecule alternatives.
• Targeting TNF-α is crucial for treating autoimmune and inflammatory diseases.

Purpose of the Study:

• To identify novel small molecule inhibitors of TNF-α using in silico methods.
• To evaluate the binding interactions and stability of potential inhibitors.
• To assess the pharmacokinetic and toxicity profiles of identified compounds.

Main Methods:

• Pharmacophore modeling and virtual screening of large compound libraries.
• Molecular docking to assess binding affinity and interactions.
• Molecular dynamics simulations to evaluate compound stability.
• In silico ADMET analysis for pharmacokinetic and toxicity prediction.

Main Results:

• Identified three potent lead compounds (ZINC05848961, ZINC09402309, ZINC04502991) targeting the TNF receptor (TNFR).
• Confirmed stable interactions and effective blockage of TNF production via molecular dynamics.
• Predicted favorable pharmacokinetic properties (high GI absorption, good bioavailability) and low toxicity for most compounds.

Conclusions:

• The identified small molecules represent promising candidates for developing new TNF-α-targeted therapies.
• These compounds offer a potential alternative to existing antibody-based treatments with improved safety.
• The study provides a foundation for further preclinical development of novel anti-inflammatory agents.