Exploring the C-domain inhibition of angiotensin converting enzyme through novel bradykinin potentiating peptides
Kerly Fernanda Mesquita Pasqualoto · Pharmacy & Pharmacology International Journal · 2018
Background: Proline-rich oligopeptides (PRO) presenting antihypertensive effects have been found in snake venoms.They can be selective to the C-terminal domain of angiotensin converting enzyme (ACE) binding site and quite potent competitive inhibitors regarding the angiotensin I cleavage, as well.The main structural features of PRO ligands comprise: a pyroglutamyl residue at the N-terminal portion, a high content of proline residues, and the tripeptide Ile-Pro-Pro at the C-terminal moiety.Objective: A set of eight PRO compounds from venom of Bitis and Bothrops genus was investigated, herein, using molecular docking and structure-property approaches to explore the ACE C-terminal domain.Method: Eight PRO compounds were selected according to the respective inhibition constant value against the ACE enzyme.The coordinates of the human ACE/BPP complex were retrieved from Protein Data Bank (PBD ID 4APJ; resolution at 2.60 Å) and used as reference to perform the molecular docking simulations, using CLC Drug Discovery Workbench 2.4 software.The three-dimensional (3D) structure of the ligand in the 4APJ complex was considered as starting geometry to build up the eight PRO molecular models. Results:The compound PRO8 presented favorable calculated binding affinity, but compounds containing additional amino acid residues at the C-terminal moiety, such as PRO2 and PRO4, have showed poor docking score values, meaning the ligand-enzyme complex formation was energetically unfavorable.Perspectives: Since BPPs have been reported as multi-target compounds, the novel promising compound, PRO8, from Bitis nasicornis venom, can be optimized and drive the rational design of antihypertensive drug candidates considering the two pathways involved in BPPs' hypotensive effects.