Development of 4′-Oxo-MLN4924 as potential neddylation inhibitors: Design, synthesis, anti-HCMV evaluation, and molecular docking

초록

MLN4924 (1), 1 ), a neddylation inhibitor, has shown promising anticancer and antiviral properties. In this study, we designed and synthesized new derivatives of 4 '-oxo- '-oxo- MLN4924, inspired by the structures of MLN4924 and another known neddylation inhibitor, referred to as compound 2 . Like compound 2 , we used a specific type of sugar molecule but incorporated a modified building block known as 7-deazapurine for the nucleobase part. Additionally, we arranged the sulfamate and 2 '-hydroxyl '-hydroxyl as key functional groups. We found that the 2 '-OH '-OH group is essential for activity against human cytomegalovirus (HCMV) using luciferase reporter assay. Molecular docking and molecular dynamics (MD) studies revealed that the conformation of the sugar moiety plays a crucial role in protein-ligand interactions. These studies suggest that derivatives with a bulky aromatic ring at the 6-position of the nucleobase are likely to have enhanced binding, which is supported by experimental findings.

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