Structure-Activity Relationships of Benzenesulfonamide-Based Inhibitors towards Carbonic Anhydrase Isoform...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Structural Biology

Background:

• Carbonic anhydrases (CAs) are crucial enzymes involved in various physiological processes.
• Dysregulation of specific CA isoforms, such as CA IX and XII, is linked to aggressive cancers.
• Developing isoform-selective CA inhibitors is essential for targeted cancer therapy with reduced side effects.

Purpose of the Study:

• To design and synthesize novel benzenesulfonamide-based inhibitors targeting disease-associated carbonic anhydrase isoforms.
• To elucidate the structural basis of inhibitor binding and selectivity across different CA isoforms.
• To provide insights for the rational design of potent and selective small molecule CA inhibitors.

Main Methods:

• Synthesis of four benzenesulfonamide-based inhibitors utilizing a tail approach.
• Determination of crystal structures of inhibitors bound to CA IX mimic and CA II.
• In silico modeling, including docking studies into CA I and XII.
• Computational analysis of inhibitor conformations and binding interactions.

Main Results:

• Synthesized inhibitors exhibited nanomolar affinities for various CA isoforms.
• Crystal structures revealed key interactions within the active site, particularly involving residues at positions 92 and 131.
• In silico modeling identified specific residues influencing binding affinity and selectivity.
• Tail groups of the inhibitors were found to modulate CA isoform specificity.

Conclusions:

• Active-site residues, especially in the hydrophobic pocket, are critical determinants of inhibitor binding and affinity.
• Tail modifications on benzenesulfonamide inhibitors can achieve carbonic anhydrase isoform selectivity.
• These findings advance the understanding of designing selective small molecule inhibitors for therapeutic applications.