From Far West to East: Joining the Molecular Architecture of Imidazole-like Ligands in HO-1 Complexes

• Main Authors: Giuseppe Floresta (Author), Antonino Nicolò Fallica (Author), Vincenzo Patamia (Author), Valeria Sorrenti (Author), Khaled Greish (Author), Antonio Rescifina (Author), Valeria Pittalà (Author)
• Format: Book
• Published: MDPI AG, 2021-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph14121289; 1424-8247
• Keywords: fragment-based ligand design; fragment growing; ligand joining; structure-based drug design; heme oxygenase; HO-1 inhibitors; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 14, Iss 12, p 1289 (2021)

HO-1 overexpression has been reported in several cases/types of human malignancies. Unfortunately, poor clinical outcomes are reported in most of these cases, and the inhibition of HO-1 is considered a valuable and proven anticancer approach. To identify novel hit compounds suitable as HO-1 inhibitors, we report here a fragment-based approach where ligand joining experiments were used. The two most important parts of the classical structure of the HO-1 inhibitors were used as a starting point, and 1000 novel compounds were generated and then virtually evaluated by structure and ligand-based approaches. The joining experiments led us to a novel series of indole-based compounds. A synthetic pathway for eight selected molecules was designed, and the compounds were synthesized. The biological activity revealed that some molecules reach the micromolar activity, whereas molecule <b>4d</b> inhibits the HO-1 with an IC₅₀ of 1.03 μM. This study suggested that our joining approach was successful, and a novel hit compound was generated. These results are ongoing for further development.