Heteroaryldihydropyrimidines Alter Capsid Assembly by Adjusting the Binding Affinity and Pattern of the Hepatitis B Virus Core Protein

Huihui Liu, Susumu Okazaki, Wataru Shinoda

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)


Hepatitis B virus (HBV) infections are a major global health concern, for which heteroaryldihydropyrimidines (HAPs) have been developed. HAPs accelerate and/or result in aberrant capsid assembly; however, their effect on the assembly mechanism is unknown. This study aimed to compare the effects of three representative HAPs on core protein dimer assembly through molecular dynamics simulations and free energy calculations. Molecular docking and equilibrium simulations showed that different HAPs bind at the same binding site and are involved in different interactions. The observed conformational changes in HAPs deter the calculation of binding affinity. Herein, the reduced free energy perturbation/Hamiltonian replica exchange molecular dynamics method was used to enhance sampling during binding affinity calculations, indicating consistency between the binding free energies of HAPs and pEC50. Furthermore, binding pattern analysis revealed that the tetramer could sample flat structures after binding HAPs. The present results suggest a mechanism wherein HAPs accelerate capsid assembly by increasing the binding affinity of dimers, leading to aberrant assembly by altering the binding orientation of dimers.

Original languageEnglish
Pages (from-to)5104-5110
Number of pages7
JournalJournal of Chemical Information and Modeling
Issue number12
Publication statusPublished - Dec 23 2019
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences


Dive into the research topics of 'Heteroaryldihydropyrimidines Alter Capsid Assembly by Adjusting the Binding Affinity and Pattern of the Hepatitis B Virus Core Protein'. Together they form a unique fingerprint.

Cite this