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Pentacycloundecane lactam vs lactone norstatine type HIV protease inhibitors : binding energy calculations and DFT study. B.Honarparvar , H.G . Kruger, T. Govender , G.E . M. Maguire - PowerPoint PPT Presentation
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Pentacycloundecane lactam vs lactone norstatine type HIV protease inhibitors:
binding energy calculations and DFT study
B.Honarparvar, H.G. Kruger, T. Govender, G.E. M. Maguire
Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, South Africa
December 2013
Structures of PCU-lactam-EAIS, its tautomer PCU-lactim-EAIS, PCU-lactone-EAIS inhibitors and PCU-models
HN OHN
OHONH
OOH
O
HN
O
NHO
H2NOH
PCU-Lactim-NH-EAIS
NHOH
O
O
OO
HN
O
NHHN
O
OOH
OH
O
H2N
IC50= 0.850 µMPCU-Lactone-CO-EAIS
HN OHHN
OONH
OOH
O
HN
O
NHO
H2NOH
PCU-Lactam-NH-EAISIC50= 0.076 µM
NHOH
HN
O
OO
HN
O
NHHN
O
OOH
OH
O
H2N
PCU-Lactone-NH-EAIS
HN OHO
OONH
OOH
O
HN
O
NHO
H2NOH
PCU-Lactam-CO-EAIS
NHOH
N
O
OHO
HN
O
NHHN
O
OOH
OH
O
H2N
PCU-Lactim-CO-EAIS
HN OHN
OHOH3C
PCU-lactim
HN OHHN
OOH3C
NHOH
O
O
H3CO
PCU-lactone
PCU-lactam
MD simulation
Binding free energy calculations
DFT study
Objectives
Software: Amber12
Method: MMPB(GB)SA
Binding free energy calculations
PCU- peptide inhibitor inside the active site of South African HIV protease
PCU-peptide inhibitor docked to HIV protease
The MM-PB(GB)SA method can be conceptually summarized as:
ΔGbind = Gcomplex – (Genzyme + Gligand)
where Gcomplex, Genzyme and Gligand are the free energies of the complex, the enzyme and the ligand, respectively.
MM-PB(GB)SA binding free energy calculations
Binding free energies and its components for the PCU-models complexed with the HIV protease
PCU-models ΔEELE ΔEVDW
ΔESOL(
PB)
ΔESOL(G
B)
ΔGbind(PB
SA)
ΔGbind(GBS
A)
PCU-lactam(a) -1.48 -34.13 28.73 11.34 -29.52 -27.63
PCU-lactam(b) -1.88 -30.14 22.44 14.99 -29.69 -19.99
PCU-lactim(a) -12.23 -30.14 33.92 21.01 -29.85 -24.78
PCU-lactim(b) -9.52 -31.07 33.63 22.76 -27.85 -20.98
PCU-lactone(a) -2.51 -25.61 16.95 13.34 -28.19 -17.37
PCU-lactone(b) -5.30 -27.26 18.40 17.53 -23.39 -17.92
HN OHN
OHOH3C
PCU-lactim
HN OHHN
OOH3C NH
OHO
O
H3CO
PCU-lactonePCU-lactam
Binding free energies and its components for the PCU-peptides complexed with the HIV protease
PCU-peptides ΔEELE ΔEVDW
ΔESOL(
PB)
ΔESOL(G
B)
ΔGbind(PB
SA)
ΔGbind(G
BSA)PCU-lactam-NH-EAIS(a) -29.39 -68.41 52.81 53.46 -69.79 -61.74
PCU-lactam-NH-EAIS(b) -19.65 -60.67 49.97 41.95 -64.39 -43.19
PCU-lactim-NH-EAIS(a) -30.39 -71.48 80.90 55.23 -68.07 -54.33
PCU-lactim-NH-EAIS(b) -21.94 -68.36 62.31 43.20 -72.54 -54.48
PCU-lactone-CO-EAIS(a) -24.22 -55.02 93.73 87.38 -61.77 -37.99
PCU-lactone-CO-EAIS(b)-29.39 -68.41 52.81 53.46 -69.79 -61.74
NHOH
O
O
OO
HN
O
NHHN
O
OOH
OH
O
H2N
IC50= 0.850 µMPCU-Lactone-CO-EAIS
HN OHHN
OONH
OOH
O
HN
O
NHO
H2NOH
PCU-Lactam-NH-EAISIC50= 0.076 µM
Binding free energies and its components for the synthesized PCU-peptides complexed with the HIV
protease
PCU-peptides ΔEELE ΔEVDW
ΔESOL(
PB)
ΔESOL(G
B)
ΔGbind(PB
SA)
ΔGbind(
GBSA)PCU-lactam-CO-EAIS(a) -23.21 -74. 82 117.34 106.88 -87.89 -58.79
PCU-lactam-CO-EAIS(b) -28.45 -69.76 123.84 99.49 -61.99 -40.02
PCU-lactim-CO-EAIS(a) -11.87 -59.99 56.69 37.49 -55.37 -55.99
PCU-lactim-CO-EAIS(b) -21.94 -68.36 62.31 43.20 -54.77 -72.54
PCU-lactone-NH-EAIS(a) -19.50 -74.31 73.49 46.27 -67.41 -55.34
PCU-lactone-NH-EAIS(b)-9.01 -74.08 52.55 34.55 -78.71 -57.10
NHOH
HN
O
OO
HN
O
NHHN
O
OOH
OH
O
H2N
PCU-Lactone-NH-EAIS
HN OHO
OONH
OOH
O
HN
O
NHO
H2NOH
PCU-Lactam-CO-EAIS
Software: Gaussian09
Method: B3LYP
Basis set: 6-311G**
DFT study of PCU-models
HN OHN
OHOH3C
PCU-lactim
HN OHHN
OOH3C NH
OHO
O
H3CO
PCU-lactonePCU-lactam
Electronic structure properties
NBO AnalysisPolarizability Electrostatic Potential Map
(HOMO- LUMO) Natural atomic charges
Natural atomic charges (a.u.) on nitrogen and oxygen nuclei of PCU-models
Atom Lactam Lactim Lactone
N1/O1 -0.65213 -0.56236 -0.58068
O2 -0.63617 -0.69693 -0.59012
O3 -0.74727 -0.73899 -0.73981
N4 -0.65298 -0.65717 -0.60787
O5 -0.63987 -0.62519 -0.65063
HN OHHN
OONH
OHO
O
O
PCU-lactam PCU-lactone
12
3
4
51
2
34
5
HN OHN
OH
PCU-lactim
O 12
3
4
5
Electrostatic Potential Map
PCU-lactim
PCU-lactam PCU-lactone
The frontiers orbitals of PCU-models
(a) HOMO for Lactam (b) LUMO for Lactam
(a) HOMO for Lactim (b) LUMO for Lactim
(a) HOMO for Lactone (b) LUMO for Lactone
Polarizability (Å3), dipole moment (Debye) and Gibbs free solvation energy ∆Gsolv (kcal/mol) values
of the PCU-models
PCU-models α (Å3) µ (Debye)∆GSolv
(kcal/mol)
PCU-lactam 81.218 6.4726 -17.925
PCU-lactim 81.663 3.5616-17.085
PCU-lactone 79.324 1.2617 -8.893
Acknowledgements
We thank the National Research Foundation for financial support, UKZN, and the CHPC (www.chpc.ac.za) for computational resources.
Thank you for your kind attention
