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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 the conformational stabilization of the protein molecule in its closed form is highly correlated with the ligands activity and can be used to predict their potency. Hence, predicting inhibitor potency in silico might depend on modeling the conformational changes of the protein molecule upon binding of the ligand rather than estimating the changes in free binding energy that arise from their interaction.

SUBMITTER: Spassov DS

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

REPOSITORIES: biostudies-literature

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

Spassov Danislav S DS Atanasova Mariyana M Doytchinova Irini I

International journal of molecular sciences 20230718 14

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 t ...[more]

PMID: 37511367

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Project description:BackgroundHIV protease inhibitor (PI) therapy results in the rapid selection of drug resistant viral variants harbouring one or two substitutions in the viral protease. To combat PI resistance development, two approaches have been developed. The first is to increase the level of PI in the plasma of the patient, and the second is to develop novel PI with high potency against the known PI-resistant HIV protease variants. Both approaches share the requirement for a considerable increase in the number of protease mutations to lead to clinical resistance, thereby increasing the genetic barrier. We investigated whether HIV could yet again find a way to become less susceptible to these novel inhibitors.Methods and findingsWe have performed in vitro selection experiments using a novel PI with an increased genetic barrier (RO033-4649) and demonstrated selection of three viruses 4- to 8-fold resistant to all PI compared to wild type. These PI-resistant viruses did not have a single substitution in the viral protease. Full genomic sequencing revealed the presence of NC/p1 cleavage site substitutions in the viral Gag polyprotein (K436E and/or I437T/V) in all three resistant viruses. These changes, when introduced in a reference strain, conferred PI resistance. The mechanism leading to PI resistance is enhancement of the processing efficiency of the altered substrate by wild-type protease. Analysis of genotypic and phenotypic resistance profiles of 28,000 clinical isolates demonstrated the presence of these NC/p1 cleavage site mutations in some clinical samples (codon 431 substitutions in 13%, codon 436 substitutions in 8%, and codon 437 substitutions in 10%). Moreover, these cleavage site substitutions were highly significantly associated with reduced susceptibility to PI in clinical isolates lacking primary protease mutations. Furthermore, we used data from a clinical trial (NARVAL, ANRS 088) to demonstrate that these NC/p1 cleavage site changes are associated with virological failure during PI therapy.ConclusionsHIV can use an alternative mechanism to become resistant to PI by changing the substrate instead of the protease. Further studies are required to determine to what extent cleavage site mutations may explain virological failure during PI therapy.

Dataset Information

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

Publications

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

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