5GMZ

Hepatitis B virus core protein Y132A mutant in complex with 4-methyl heteroaryldihydropyrimidine

Summary for 5GMZ

• Entry DOI: 10.2210/pdb5gmz/pdb
• Descriptor: Core protein, ISOPROPYL ALCOHOL, (2S)-4,4-difluoro-1-[[(4S)-4-(4-fluorophenyl)-5-methoxycarbonyl-4-methyl-2-(1,3-thiazol-2-yl)-1H-pyrimidin-6-yl]methyl]pyrrolidine-2-carboxylic acid, ... (6 entities in total)
• Functional Keywords: hbv, capid assembly, hap, core protein, viral protein
• Biological source: Hepatitis B virus (HBV)
• Total number of polymer chains: 6
• Total formula weight: 109263.59

Authors

Xu, Z.H.,Zhou, Z. (deposition date: 2016-07-18, release date: 2016-08-10, Last modification date: 2024-10-16)

Primary citation

Qiu, Z.,Lin, X.,Zhou, M.,Liu, Y.,Zhu, W.,Chen, W.,Zhang, W.,Guo, L.,Liu, H.,Wu, G.,Huang, M.,Jiang, M.,Xu, Z.,Zhou, Z.,Qin, N.,Ren, S.,Qiu, H.,Zhong, S.,Zhang, Y.,Zhang, Y.,Wu, X.,Shi, L.,Shen, F.,Mao, Y.,Zhou, X.,Yang, W.,Wu, J.Z.,Yang, G.,Mayweg, A.V.,Shen, H.C.,Tang, G.
Design and Synthesis of Orally Bioavailable 4-Methyl Heteroaryldihydropyrimidine Based Hepatitis B Virus (HBV) Capsid Inhibitors
J.Med.Chem., 59:7651-7666, 2016

PubMed Abstract: Targeting the capsid protein of hepatitis B virus (HBV) and thus interrupting normal capsid formation have been an attractive approach to block the replication of HBV viruses. We carried out multidimensional structural optimizations based on the heteroaryldihydropyrimidine (HAP) analogue Bay41-4109 (1) and identified a novel series of HBV capsid inhibitors that demonstrated promising cellular selectivity indexes, metabolic stabilities, and in vitro safety profiles. Herein we disclose the design, synthesis, structure-activity relationship (SAR), cocrystal structure in complex with HBV capsid proteins and in vivo pharmacological study of the 4-methyl HAP analogues. In particular, the (2S,4S)-4,4-difluoroproline substituted analogue 34a demonstrated high oral bioavailability and liver exposure and achieved over 2 log viral load reduction in a hydrodynamic injected (HDI) HBV mouse model.

PubMed: 27458651
DOI: 10.1021/acs.jmedchem.6b00879

Experimental method

X-RAY DIFFRACTION (1.7 Å)