Protease Inhibitors in View of Peptide Substrate Databases

Area of Science:

• Biochemistry
• Computational Chemistry
• Drug Discovery

Background:

• Protease substrate profiling is a routine experimental task.
• MEROPS database provides accessible knowledge on protease peptide substrates.

Purpose of the Study:

• To develop a shape-based virtual screening workflow using vROCS.
• To identify new small-molecule protease inhibitors by applying protease specificity information.

Main Methods:

• Utilized peptide substrate sequences from MEROPS for training set construction.
• Converted 2D substrate sequences to 3D conformations via template mutation.
• Built vROCS queries from single amino acid queries considering relative frequencies.

Main Results:

• Demonstrated good performance for thrombin, factor Xa, factor VIIa, and caspase-3 using the DUD-E dataset.
• Validated method's effectiveness across proteases with diverse specificity and active-site mechanisms.

Conclusions:

• The peptide-substrate-based virtual screening approach is effective for protease inhibitor discovery.
• This method offers significant advantages by not requiring target structure or known inhibitor information.