B.Honarparvar , H.G . Kruger, T. Govender , G.E . M. Maguire
description
Transcript of B.Honarparvar , H.G . Kruger, T. Govender , G.E . M. Maguire
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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
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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
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MD simulation
Binding free energy calculations
DFT study
Objectives
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Software: Amber12
Method: MMPB(GB)SA
Binding free energy calculations
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PCU- peptide inhibitor inside the active site of South African HIV protease
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PCU-peptide inhibitor docked to HIV protease
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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
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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
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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
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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
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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
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Electronic structure properties
NBO AnalysisPolarizability Electrostatic Potential Map
(HOMO- LUMO) Natural atomic charges
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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
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Electrostatic Potential Map
PCU-lactim
PCU-lactam PCU-lactone
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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
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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
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Acknowledgements
We thank the National Research Foundation for financial support, UKZN, and the CHPC (www.chpc.ac.za) for computational resources.
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Thank you for your kind attention