Inhibitor Trapping in N-Myristoyltransferases as a Mechanism for Drug Potency.

ABSTRACT: Predicting inhibitor potency is critical in drug design and development, yet it has remained one of computational biology's biggest unresolved challenges. Here, we show that in the case of the N-myristoyltransferase (NMT), this problem could be traced to the mechanisms by which the NMT enzyme is inhibited. NMT adopts open or closed conformations necessary for orchestrating the different steps of the catalytic process. The results indicate that the potency of the NMT inhibitors is determined by their ability to stabilize the enzyme conformation in the closed state, and that in this state, the small molecules themselves are trapped and locked inside the structure of the enzyme, creating a significant barrier for their dissociation. By using molecular dynamics simulations, we demonstrate that

SUBMITTER: Spassov DS 

PROVIDER: S-EPMC10380619 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature