Novel lead structures for p38 MAP kinase via FieldScreen virtual screening.

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• p38 MAP kinase is a significant target for anti-inflammatory drug development.
• Existing p38 inhibitors often share similar chemical scaffolds, necessitating novel structural approaches.

Purpose of the Study:

• To identify novel, structurally distinct inhibitors of p38 MAP kinase.
• To discover potential lead compounds for the treatment of inflammatory diseases.

Main Methods:

• Ligand-based virtual screening using the FieldScreen technique on over 1.2 million compounds.
• Selection of 58 diverse compounds based on molecular field similarity, excluding known scaffolds.
• Biological evaluation of selected compounds for p38 inhibition.
• Structure-activity relationship (SAR) analysis using FieldAlign modeling.

Main Results:

• 11 out of 58 tested compounds (19%) demonstrated significant p38 inhibition (>or=20% at 10 microM).
• Two distinct chemical series were explored through analogue preparation.
• A potential lead compound with a pIC(50) of 6.4 was identified.
• SAR of thiadiazole-based inhibitors was rationalized via modeling.

Conclusions:

• Novel p38 inhibitors can be effectively discovered using scaffold-hopping virtual screening strategies.
• The identified lead compound and SAR data provide a foundation for further optimization in anti-inflammatory drug discovery.
• FieldScreen and FieldAlign are valuable tools for identifying and characterizing novel kinase inhibitors.