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

Abstract

BackgroundNovel 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.ResultsThe 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.ConclusionsA 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-015-0115-5) contains supplementary material, which is available to authorized users.

Structure-Based Designing, Solvent Less Synthesis of 1,2,3,4-Tetrahydropyrimidine-5-carboxylate Derivatives: A Combined In Vitro and In Silico Screening Approach

“…A high value of dipole moment of compound 5f is an indication of fine charge distribution and bond distance adjusted well. This explains that the molecule showing the process of oxidation reflects the best conductivity [ 38 , 42 , 43 , 44 ].…”

Analysis of Conformational, Structural, Magnetic, and Electronic Properties Related to Antioxidant Activity: Revisiting Flavan, Anthocyanidin, Flavanone, Flavonol, Isoflavone, Flavone, and Flavan-3-ol

“… 69 DFT has been a useful method to study the structural, electronic, and magnetic molecular properties of compounds. 16 , 37 , 58 , 70 − 72 The CAM-B3LYP functional was used with the split valence def2TZV basis set of Ahlrichs et al (CAM-B3LYP/def2TZV). 73 − 76 We selected the CAM-B3LYP functional due to its well-established and useful application to investigate chemical structures.…”

“…The self-consistent field calculations of flavonoid structures were performed using DFT . DFT has been a useful method to study the structural, electronic, and magnetic molecular properties of compounds. ,,,− The CAM-B3LYP functional was used with the split valence def2TZV basis set of Ahlrichs et al (CAM-B3LYP/def2TZV). − We selected the CAM-B3LYP functional due to its well-established and useful application to investigate chemical structures . The correlation consistent cc-pVDZ basis set was also applied to study the aromaticity and the oxidation of the aromatic ring in the flavonoid structures .…”

Characterization of stenocephol from Seriphidium stenocephalum as potent HepG2 cell growth and glycogen phosphorylase inhibitor

“…A large negative value of electronic energy (E) indicates the stability of stenocephol, which referred to the Coulombic forces, dipole-dipole interactions and hydrogen bonds contributed towards the higher binding affinity, more solute-solvent interactions, and low IC50 value (Honarparvar et al 2015). The coordinates of the compounds, optimized bond lengths and angles, are reported in Tables S4 and S5.…”