Cargando…

Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study

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 IC(50) values of less than 1.00 μM. A comparative MM-PB(GB)SA b...

Descripción completa

Detalles Bibliográficos
Autores principales: Honarparvar, Bahareh, Pawar, Sachin A, Alves, Cláudio Nahum, Lameira, Jerônimo, Maguire, Glenn EM, Silva, José Rogério A, Govender, Thavendran, Kruger, Hendrik G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387594/
https://www.ncbi.nlm.nih.gov/pubmed/25889635
http://dx.doi.org/10.1186/s12929-015-0115-5
_version_ 1782365289451618304
author Honarparvar, Bahareh
Pawar, Sachin A
Alves, Cláudio Nahum
Lameira, Jerônimo
Maguire, Glenn EM
Silva, José Rogério A
Govender, Thavendran
Kruger, Hendrik G
author_facet Honarparvar, Bahareh
Pawar, Sachin A
Alves, Cláudio Nahum
Lameira, Jerônimo
Maguire, Glenn EM
Silva, José Rogério A
Govender, Thavendran
Kruger, Hendrik G
author_sort Honarparvar, Bahareh
collection PubMed
description 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 IC(50) 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 (IC(50)) 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 (IC(50) = 0.076 μM) and the PCU-lactone-CO-EAIS peptide inhibitors (IC(50) = 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 (∆G(solv)) 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 IC(50) data. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12929-015-0115-5) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-4387594
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-43875942015-04-08 Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study Honarparvar, Bahareh Pawar, Sachin A Alves, Cláudio Nahum Lameira, Jerônimo Maguire, Glenn EM Silva, José Rogério A Govender, Thavendran Kruger, Hendrik G J Biomed Sci Research 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 IC(50) 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 (IC(50)) 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 (IC(50) = 0.076 μM) and the PCU-lactone-CO-EAIS peptide inhibitors (IC(50) = 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 (∆G(solv)) 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 IC(50) data. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12929-015-0115-5) contains supplementary material, which is available to authorized users. BioMed Central 2015-02-18 /pmc/articles/PMC4387594/ /pubmed/25889635 http://dx.doi.org/10.1186/s12929-015-0115-5 Text en © Honarparvar et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Honarparvar, Bahareh
Pawar, Sachin A
Alves, Cláudio Nahum
Lameira, Jerônimo
Maguire, Glenn EM
Silva, José Rogério A
Govender, Thavendran
Kruger, Hendrik G
Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study
title Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study
title_full Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study
title_fullStr Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study
title_full_unstemmed Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study
title_short Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study
title_sort pentacycloundecane lactam vs lactone norstatine type protease hiv inhibitors: binding energy calculations and dft study
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387594/
https://www.ncbi.nlm.nih.gov/pubmed/25889635
http://dx.doi.org/10.1186/s12929-015-0115-5
work_keys_str_mv AT honarparvarbahareh pentacycloundecanelactamvslactonenorstatinetypeproteasehivinhibitorsbindingenergycalculationsanddftstudy
AT pawarsachina pentacycloundecanelactamvslactonenorstatinetypeproteasehivinhibitorsbindingenergycalculationsanddftstudy
AT alvesclaudionahum pentacycloundecanelactamvslactonenorstatinetypeproteasehivinhibitorsbindingenergycalculationsanddftstudy
AT lameirajeronimo pentacycloundecanelactamvslactonenorstatinetypeproteasehivinhibitorsbindingenergycalculationsanddftstudy
AT maguireglennem pentacycloundecanelactamvslactonenorstatinetypeproteasehivinhibitorsbindingenergycalculationsanddftstudy
AT silvajoserogerioa pentacycloundecanelactamvslactonenorstatinetypeproteasehivinhibitorsbindingenergycalculationsanddftstudy
AT govenderthavendran pentacycloundecanelactamvslactonenorstatinetypeproteasehivinhibitorsbindingenergycalculationsanddftstudy
AT krugerhendrikg pentacycloundecanelactamvslactonenorstatinetypeproteasehivinhibitorsbindingenergycalculationsanddftstudy