• 作者： Bahareh Honarparvar, Sachin A Pawar, Claudio Nahum Alves, Jeronimo Lameira, Glenn EM Maguire, Jose Rogerio A Silva, Thavendran Govender ,Hendrik G Kruger
• 作者服務機構： Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban , South Africa
• 中文摘要： --
• 英文摘要： Background:
  
  Novel pentacycloundecane (PCU)-lactone-CO-EAIS peptide inhibitors were designed,synthesized, and evaluated against wild-type C-South African (C-SA) HIV-1 protease. Three compounds are reported herein, two of which displayed IC50 values of less than 1.00 µM. A comparative MM-PB(GB)SA binding free energy of solvation values of PCU-lactam and lactone models and their enantiomers as well as the PCU-lactam-NH-EAIS and lactone-COEAIS
  peptide inhibitors and their corresponding diastereomers complexed with South African HIV protease (C-SA) were performed in order to rationalize the considerable difference between inhibitory concentration (IC50) of PCU-lactam-NH-EAIS and PCU-lactone-COEAIS peptides.
  
  
  
  Results:
  
  The PCU-lactam model exhibited more negative calculated binding free energies of solvation
  than the PCU-lactone model. The same trend was observed for the PCU-peptide inhibitors, which correspond to the experimental activities for the PCU-lactam-NH-EAIS peptide (IC50= 0.076 µM) and the PCU-lactone-CO-EAIS peptide inhibitors (IC50 = 0.850 µM). Furthermore, a density functional theory (DFT) study on the natural atomic charges of the nitrogen and oxygen atoms of the three PCU-lactam, PCU-lactim and PCU-lactone models were performed using natural bond orbital (NBO) analysis. Electrostatic potential maps were also used to visualize the electron density around electron-rich regions. The asymmetry parameter (η) and quadrupole coupling constant (χ) values of the nitrogen and oxygen nuclei of the model compounds were calculated at the same level of theory. Electronic molecular properties including polarizability and electric dipole moments were also calculated and
  compared. The Gibbs theoretical free solvation energies of solvation (∆Gsolv) were also considered.
  
  
  
  Conclusions:
  
  A general trend is observed that the lactam species appears to have a larger negative charge distribution around the heteroatoms, larger quadrupole constant, dipole moment and better solvation energy, in comparison to the PCU-lactone model. It can be argued that these characteristics will ensure better eletronic interaction between the lactam and the receptor, corresponding to the observed HIV protease activities in terms of experimental IC50 data.
• 中文關鍵字： --
• 英文關鍵字： Pentacyclo-undecane (PCU), Lactone, Lactam and lactim peptides, Human immunodeficiency virus protease (HIV PR), Inhibitory concentration (IC50), Molecular dynamics (MD), MM-PB (GB) SA method