Identification of potential tumour-associated carbonic anhydrase isozyme IX inhibitors: atom-based 3D-QSAR modelling,...

Area of Science:

• Computational chemistry
• Medicinal chemistry
• Oncology

Background:

• Tumour hypoxia induces significant changes in cancer cell behavior, including a shift to anaerobic glycolysis.
• This metabolic shift leads to microenvironmental pH changes and overexpression of carbonic anhydrase IX (CA IX) in many solid tumours.
• CA IX is a promising therapeutic target for novel anti-cancer drug development.

Purpose of the Study:

• To identify potential inhibitors of carbonic anhydrase IX (CA IX) using in silico approaches.
• To provide design insights and potential molecular scaffolds for developing new anti-cancer agents targeting CA IX.

Main Methods:

• Atom-based 3D-QSAR (Quantitative Structure-Activity Relationship) modelling was employed.
• Pharmacophore-based virtual screening of a large chemical database (ZINC 15) was performed.
• Molecular docking studies were conducted against human CA IX protein (PDB ID: 5FL6).

Main Results:

• A robust QSAR model was developed with high statistical significance (R²=0.9864, Q²=0.8799).
• Virtual screening identified 163 potential CA IX inhibitors, with ZINC02260669 and ZINC72370966 showing high ranking and predicted activity.
• Molecular docking confirmed favourable binding interactions for the top identified compounds, suggesting therapeutic potential.

Conclusions:

• Computational strategies effectively identified novel chemical scaffolds with potential as CA IX inhibitors.
• The study provides valuable insights for the rational design of targeted anti-cancer therapeutics.
• Further development of these identified compounds could lead to effective treatments for solid tumours.