In Silico Evaluation of Hypotensin’s Interaction Potential with Molecular Targets Involved in Blood Pressure Regulation

INTRODUCTION: Hypotensins are linear peptides composed of 24–25 amino acid residues and characterized by a Lys-Pro-Pro (KPP) motif at their C-terminal region. Previous studies have shown their endothelium-dependent hypotensive activity through activation of the bradykinin B2 receptor, without interaction with angiotensin-converting enzyme (ACE). Despite their structural and physicochemical similarities, hypotensins from different species differ subtly, and it remains unclear whether these peptides interact similarly with physiological targets or produce comparable biological effects. OBJECTIVE: To evaluate hypotensins' interaction potential with molecular components involved in blood pressure regulation using in silico modeling and molecular docking. METHODOLOGY: We retrieved hypotensin primary sequences from the NCBI database using keyword-based searches. Peptide structures were predicted using AlphaFold 3. We selected molecular targets based on the literature on blood pressure regulation, including angiotensin-converting enzymes ACE1 and ACE2 (PDB IDs: 1O86 and 1R42, respectively) and the bradykinin B2 receptor (B2R; PDB ID: 7F6H). We obtained target structures from the RCSB Protein Data Bank, prioritizing those with suitable quality parameters. We performed molecular docking simulations using the HADDOCK server with recommended parameters for this type of analysis. We evaluated the resulting complexes using the PLIP server and further validated and visualized them in PyMOL. RESULTS: The peptide-target complexes showed distinct molecular interaction profiles. TpHyp1(₁₄–₃₈) had the most favorable docking score for ACE2 (−119.1 ± 2.0), stabilized by seven salt bridges and five hydrogen bonds. For B2R, TsHpt-I showed the most favorable docking score (−115.8 ± 3.4; RMSD: 0.4), supported by nine hydrogen bonds. Regarding ACE1, TstiH achieved the most favorable docking score (−88.9 ± 2.8; RMSD: 0.4), supported by five hydrophobic interactions, three salt bridges, and three hydrogen bonds. CONCLUSION: The peptides showed distinct molecular interaction profiles, suggesting differential target recognition. TpHyp1(₁₄–₃₈) and TsHpt-I displayed promising interaction profiles with ACE2 and B2R, respectively. These data provide structural insights that may help guide the rational design of selective peptide-based modulators of blood pressure regulation.