Potent angiotensin-converting enzyme inhibitory tripeptides identified by a computer-based approach

Area of Science:

• Biochemistry and Medicinal Chemistry
• Computational Drug Discovery

Background:

• Angiotensin-converting enzyme (ACE) inhibitors are crucial for managing hypertension.
• Current research focuses on peptides and peptidomimetics for ACE inhibition.

Purpose of the Study:

• To identify potent ACE-inhibitory tripeptides with a proline C-terminus.
• To evaluate a novel three-step virtual screening process (tautomerization-docking-ADME simulation).

Main Methods:

• Employed a three-step virtual screening protocol: tautomerization, docking, and ADME simulation.
• Validated virtual screening results with in vitro assays.
• Investigated the impact of L-form to D-form amino acid substitutions on inhibition.

Main Results:

• Identified 16 candidate tripeptides with IC50 values ranging from 5.6 to 274.4μM.
• Reported novel ACE inhibition activity for 14 of the 16 tripeptides.
• Demonstrated that C-terminal configuration significantly impacts inhibitory activity.

Conclusions:

• The virtual screening protocol effectively identified potent ACE inhibitors.
• Identified tripeptides show comparable ACE inhibition to existing drugs but with higher predicted bioavailability.
• C-terminal proline configuration is critical for tripeptide ACE inhibitory activity, guiding rational drug design.