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Discovering novel carbonic anhydrase type IX (CA IX) inhibitors from seven million compounds using virtual screening
Ramin Ekhteiari Salmas1, Murat Senturk2, Mine Yurtsever1
1a Department of Chemistry , İstanbul Technical University , İstanbul , Turkey .
Abstract:
Carbonic anhydrase type IX (CA IX) enzyme is mostly over expressed in different cancer cell lines and tumor tissues. Potent CA IX inhibitors can be effective for adjusting the pH imbalance in tumor cells. In the present work, we represented the successful application of high throughput virtual screening (HTVS) of large dataset from ZINC database included of ∼7 million compounds to discover novel inhibitors of CA IX. HTVS and molecular docking were performed using consequence Glide/standard precision (SP), extra precision (XP) and induced fit docking (IFD) molecular docking protocols. For each compound, docking code calculates a set of low-energy poses and then exhaustively scans the binding pocket of the target with small compounds. Novel CA IX inhibitor candidates were suggested based on molecular modeling studies and a few of them were tested using in vitro analysis. These compounds were determined as good inhibitors against human CA IX target with Ki in the range of 0.85-1.58 μM. In order to predict the pharmaceutical properties of the selected compounds, ADME (absorption, distribution, metabolism and excretion) analysis was also carried out.
Insights
Researchers discovered novel carbonic anhydrase type IX (CA IX) inhibitors using high throughput virtual screening of millions of compounds. These inhibitors show promise for treating cancers by targeting pH imbalance in tumor cells.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Computational Chemistry
Background:
- Carbonic anhydrase type IX (CA IX) is overexpressed in various cancers.
- CA IX enzyme activity contributes to pH imbalance in tumor microenvironments.
- Targeting CA IX offers a potential strategy for cancer therapy.
Purpose of the Study:
- To discover novel inhibitors of carbonic anhydrase type IX (CA IX).
- To identify compounds capable of modulating tumor cell pH.
- To explore the potential of high throughput virtual screening for drug discovery.
Main Methods:
- High throughput virtual screening (HTVS) of approximately 7 million compounds from the ZINC database.
- Molecular docking studies using Glide/standard precision (SP), extra precision (XP), and induced fit docking (IFD) protocols.
- In vitro analysis and ADME (absorption, distribution, metabolism, and excretion) predictions for selected candidates.
Main Results:
- Successful identification of novel CA IX inhibitor candidates through HTVS and molecular docking.
- In vitro testing confirmed several compounds as effective inhibitors against human CA IX.
- Inhibitor candidates demonstrated inhibition constants (Ki) in the range of 0.85–1.58 μM.
- ADME analysis was performed to predict pharmaceutical properties.
Conclusions:
- High throughput virtual screening is an effective method for discovering novel CA IX inhibitors.
- Identified compounds show potential as therapeutic agents for cancers overexpressing CA IX.
- Further development of these inhibitors could lead to new treatments for managing tumor pH.
