title: Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study.
abstract: 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-CO-EAIS peptide inhibitors and their corresponding diastereomers complexed with South African HIV protease (C-SA) was performed. This will enable us to rationalize the considerable difference between inhibitory concentration (IC50) of PCU-lactam-NH-EAIS and PCU-lactone-CO-EAIS 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.
authors.affiliation: Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4041, South Africa. honarparvar@ukzn.ac.za.
authors.forename: Bahareh
authors.initials: B
authors.lastname: Honarparvar
authors.affiliation: Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4041, South Africa. sachinpawar16@gmail.com.
authors.forename: Sachin A
authors.initials: SA
authors.lastname: Pawar
authors.affiliation: Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 11101, 66075-110, Belém, PA, Brazil. nahum@ufpa.br.
authors.forename: Cláudio Nahum
authors.initials: CN
authors.lastname: Alves
authors.affiliation: Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 11101, 66075-110, Belém, PA, Brazil. jerolameira@yahoo.com.br.
authors.forename: Jerônimo
authors.initials: J
authors.lastname: Lameira
authors.affiliation: Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4041, South Africa. maguireg@ukzn.ac.za.
authors.forename: Glenn Em
authors.initials: GE
authors.lastname: Maguire
authors.affiliation: Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 11101, 66075-110, Belém, PA, Brazil. rogerioufpa@yahoo.com.br.
authors.forename: José Rogério A
authors.initials: JR
authors.lastname: Silva
authors.affiliation: Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4041, South Africa. Govenderthav@ukzn.ac.za.
authors.forename: Thavendran
authors.initials: T
authors.lastname: Govender
authors.affiliation: Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4041, South Africa. kruger@ukzn.ac.za.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Kruger
mesh_terms: D000614:Aminocaproates / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D007769:Lactams / Q000494:pharmacology*; D007783:Lactones / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry
chemical_list: D000614:Aminocaproates; D017320:HIV Protease Inhibitors; D007769:Lactams; D007783:Lactones; D010455:Peptides; C034495:3-amino-2-hydroxy-5-methylhexanoic acid