title: Exploring the binding mechanism of Heteroaryldihydropyrimidines and Hepatitis B Virus capsid combined 3D-QSAR and molecular dynamics.
abstract: The non-nucleoside drugs have been developed to treat HBV infection owing to their increased efficacy and lesser side effects, in which heteroaryldihydropyrimidines (HAPs) have been identified as effective inhibitors of HBV capsid. In this paper, the binding mechanism of HAPs targeting on HBV capsid protein was explored through three-dimensional quantitative structure-activity relationship, molecular dynamics and binding free energy decompositions. The obtained models of comparative molecular field analysis and comparative molecular similarity indices analysis enable the sufficient interpretation of structure-activity relationship of HAPs-HBV. The binding free energy analysis correlates with the experimental data. The computational results disclose that the non-polar contribution is the major driving force and Y132A mutation enhances the binding affinity for inhibitor 2 bound to HBV. The hydrogen bond interactions between the inhibitors and Trp102 help to stabilize the conformation of HAPs-HBV. The study provides insight into the binding mechanism of HAPs-HBV and would be useful for the rational design and modification of new lead compounds of HAP drugs.
authors.affiliation: College of Chemistry & Chemical Engineering, Lanzhou University, Lanzhou, 730000, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Tu
authors.affiliation: College of Chemistry & Chemical Engineering, Lanzhou University, Lanzhou, 730000, PR China.
authors.forename: Jiao Jiao
authors.initials: JJ
authors.lastname: Li
authors.affiliation: College of Chemistry & Chemical Engineering, Lanzhou University, Lanzhou, 730000, PR China; Chifeng Environmental Monitoring Center Station, Chifeng, 024000, PR China.
authors.forename: Zhi Jie
authors.initials: ZJ
authors.lastname: Shan
authors.affiliation: College of Chemistry & Chemical Engineering, Lanzhou University, Lanzhou, 730000, PR China. Electronic address: zhaihl@163.com.
authors.forename: Hong Lin
authors.initials: HL
authors.lastname: Zhai
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D002213:Capsid / Q000187:drug effects / Q000378:metabolism*; D036022:Capsid Proteins / Q000378:metabolism*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D036022:Capsid Proteins; D011743:Pyrimidines
keywords: Binding free energy; HBV capsid protein; Heteroaryldihydropyrimidines (HAPs); Molecular dynamics; Quantitative structure-activity relationship