Optimization and validation of a docking-scoring protocol; application to virtual screening for COX-2 inhibitors

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Enzyme Inhibition

Background:

• Cyclooxygenase (COX) enzymes are crucial drug targets, particularly for anti-inflammatory and analgesic medications.
• Virtual screening using structural information offers an efficient method for identifying novel enzyme inhibitors from large chemical libraries.

Purpose of the Study:

• To develop and validate a robust docking-scoring protocol for virtual screening of cyclooxygenase inhibitors.
• To assess the accuracy of the screening protocol using known active and inactive compounds.

Main Methods:

• Tuning and validation of a docking-scoring protocol using the DOCK algorithm.
• Investigation and optimization of key DOCK algorithm parameters.
• Rescoring of generated complexes using multiple scoring functions, including DOCK energy and SCORE.
• Application of a consensus approach to further enhance screening performance.

Main Results:

• Significant improvements in screening accuracy were achieved by optimizing DOCK algorithm parameters.
• DOCK energy and SCORE demonstrated good performance for cyclooxygenase.
• A consensus approach further refined the screening results.
• Initial screening of a compound library identified several potent COX inhibitors, with one-third of tested compounds showing significant enzyme inhibition.

Conclusions:

• The developed and validated docking-scoring protocol is effective for virtual screening of cyclooxygenase inhibitors.
• The study highlights the importance of parameter optimization and rescoring in virtual screening accuracy.
• This computational approach successfully identified novel compounds with significant cyclooxygenase inhibitory activity.