Extensive Reliability Evaluation of Docking-Based Target-Fishing Strategies

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• Identifying protein targets for small molecules is crucial for understanding drug mechanisms and preventing adverse effects.
• Experimental target-fishing is often infeasible due to the vast number of potential protein targets.
• In silico methods, particularly receptor-based approaches using crystallographic data, offer a promising alternative.

Purpose of the Study:

• To extensively assess the reliability of docking-based target-fishing strategies.
• To benchmark the performance of various docking procedures in identifying correct protein targets.
• To develop and evaluate a consensus docking-based target-fishing strategy.

Main Methods:

• Selected a set of X-ray protein structures from diverse targets.
• Created a dataset of known active ligands for each target.
• Built a benchmark database for evaluating 13 different docking procedures.
• Developed and tested a consensus docking strategy.

Main Results:

• The study provides the first extensive performance assessment of docking-based target-fishing.
• Identified that specific protein features can influence the reliability of docking protocols.
• Demonstrated that docking-based strategies are valuable tools within their applicable domain.

Conclusions:

• Docking-based target-fishing is a reliable approach for identifying drug targets.
• This work lays the foundation for developing more efficient receptor-based target-fishing strategies.
• The findings will aid in drug repurposing and the prediction of drug candidate off-targets.