N-myristoyltransferase 1 Inhibitors

N-myristoyltransferase 1 (NMT1) inhibitors represent a class of chemical compounds designed to target and inhibit the enzymatic activity of N-myristoyltransferase 1, an essential enzyme responsible for the covalent attachment of myristic acid to the N-terminal glycine of substrate proteins. This post-translational modification, known as N-myristoylation, plays a critical role in regulating the localization, stability, and function of a diverse range of proteins, particularly those involved in signaling pathways, cell growth, and cellular differentiation. NMT1, as one of two N-myristoyltransferase isoforms, catalyzes the transfer of the 14-carbon fatty acid (myristate) from myristoyl-coenzyme A (myristoyl-CoA) to the protein substrate, facilitating its membrane association and influencing its functional activity within cellular environments. Inhibiting NMT1 interrupts this process, impacting the overall protein functionality and altering cellular processes such as signal transduction and protein-protein interactions.

Structurally, NMT1 inhibitors are often characterized by their ability to bind competitively to the active site of the enzyme, preventing the binding of myristoyl-CoA or the substrate protein. These inhibitors generally possess hydrophobic regions that mimic the fatty acyl chain of myristic acid, allowing them to interact favorably with the enzyme's substrate-binding pocket. Additionally, many of these inhibitors include polar moieties or specific functional groups that enhance binding affinity through hydrogen bonding or ionic interactions with residues in the active site. Some of these inhibitors are highly selective for NMT1 over its isoform NMT2, providing a targeted approach for studying the specific biological pathways regulated by NMT1. The development and optimization of NMT1 inhibitors involve detailed structure-activity relationship (SAR) studies to fine-tune their binding properties and inhibitory efficacy, making them valuable tools for probing the biochemical mechanisms involving NMT1-catalyzed protein modifications.