Molecular Modeling Studies on Carbazole Carboxamide Based BTK Inhibitors Using Docking and Structure-Based 3D-QSAR

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Rheumatology

Background:

• Rheumatoid arthritis (RA) is a chronic inflammatory disease inadequately treated by current therapies.
• Bruton's tyrosine kinase (BTK) is a validated target for autoimmune diseases like RA.
• Carbazole derivatives represent a promising class of BTK inhibitors, with BMS-986142 being the only one approved for RA.

Purpose of the Study:

• To design novel, highly potent carbazole inhibitors targeting BTK for rheumatoid arthritis.
• To explore the structure-activity relationships of carbazole carboxamide derivatives against BTK.
• To identify key structural modifications for improving inhibitory activity.

Main Methods:

• Utilized molecular docking and 3D-QSAR (CoMFA and CoMSIA) to analyze 132 carbazole derivatives.
• Developed and validated predictive models for BTK inhibitory activity.
• Interpreted CoMFA/CoMSIA contour maps to understand structure-activity relationships.

Main Results:

• Established robust CoMFA (q²=0.761, r²=0.933) and CoMSIA (q²=0.891, r²=0.988) models with high predictive accuracy.
• Contour maps indicated that bulky substitutions at R₁ and hydrogen-bond donors at the 1-position enhance activity.
• Hydrophilic substitutions at R₁ and R₄ positions are crucial for improved BTK inhibition.

Conclusions:

• The study successfully identified key structural requirements for potent BTK inhibition by carbazole derivatives.
• Findings provide a rational basis for designing next-generation BTK inhibitors for rheumatoid arthritis.
• This research contributes to the development of more effective treatments for RA and other autoimmune conditions.