The Mechanism of Action of Hepatitis B Virus Capsid Assembly Modulators Can Be Predicted from Binding to Early Assembly Intermediates.
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
24 03 2022
24 03 2022
Historique:
pubmed:
16
3
2022
medline:
12
4
2022
entrez:
15
3
2022
Statut:
ppublish
Résumé
Interfering with the self-assembly of virus nucleocapsids is a promising approach for the development of novel antiviral agents. Applied to hepatitis B virus (HBV), this approach has led to several classes of capsid assembly modulators (CAMs) that target the virus by either accelerating nucleocapsid assembly or misdirecting it into noncapsid-like particles, thereby inhibiting the HBV replication cycle. Here, we have assessed the structures of early nucleocapsid assembly intermediates, bound with and without CAMs, using molecular dynamics simulations. We find that distinct conformations of the intermediates are induced depending on whether the bound CAM accelerates or misdirects assembly. Specifically, the assembly intermediates with bound misdirecting CAMs appear to be flattened relative to those with bound accelerators. Finally, the potency of CAMs within the same class was studied. We find that an increased number of contacts with the capsid protein and favorable binding energies inferred from free energy perturbation calculations are indicative of increased potency.
Identifiants
pubmed: 35290049
doi: 10.1021/acs.jmedchem.1c02040
pmc: PMC9026740
mid: NIHMS1797190
doi:
Substances chimiques
Antiviral Agents
0
Capsid Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
4854-4864Subventions
Organisme : NIAID NIH HHS
ID : P30 AI050409
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI132833
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI148740
Pays : United States
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