Ligand-based drug design for human endothelin converting enzyme-1 inhibitors

The endothelin converting enzyme-1 (ECE-1) is a zinc binding protein involved in the generation of a 21 amino acid endothelin-1 (ET-1) peptide. The mitogenic action of ET-1 has been shown in several cell types and produced by several human cancer cell lines. We have used the ligand-based drug design methods to understand the structure–activity relationship for inhibitor design of this important multi-disease target. The molecular docking of thiol-based inhibitors into the active site of ECE-1 identified several nonbonding interactions that stabilize the protein-inhibitor complex. The S1 and S1′ sub-sites could accommodate larger hydrophobic substitutions on the inhibitor with highest activity (molecule 16). From the 3D-QSAR studies, the electrostatic and steric descriptors that correlate with the activity of the inhibitors were identified. In the best pharmacophore, the hydrogen bond donor feature at the electronegative sulfur atom of inhibitor indicates that chelation with the Zn-ion is essential in the S1 sub-site, besides the other features. Together, the results from these diverse methods are complementary to each other and provide guidelines for the design of better ECE-1 inhibitors.