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
Honarparvar@ukzn.ac.za
December 2013
Structures of PCU-lactam-EAIS, its tautomer PCU-lactimEAIS, PCU-lactone-EAIS inhibitors and PCU-models
OH
OH
O
O
HN
OH
NH
O
OH
N
O
NH
O
O
OH
NH HN
NH HN
H2 N
H2 N
HN
O O
HN
O O
O
OH
OH
PCU-Lactam-NH-EAIS
PCU-Lactim-NH-EAIS
IC50= 0.076 µM
OH
O
O
OH
NH
H
N
O
O
OH
H 2N
O
O
NH HN
O
O
PCU-Lactone-CO-EAIS
IC50= 0.850 µM
OH
OH
O
O
O
O
OH
OH
NH
NH HN
O
H 2N
H
N
O
NH HN
O
OH
O
O
O
O
PCU-Lactim-CO-EAIS
PCU-Lactam-CO-EAIS
OH
O
HN
OH
O
O O
NH
O
O
O
NH HN
H2 N
OH
PCU-Lactone-NH-EAIS
HN
H3 C
HN
OH
H3 C
HN
O
N
OH
NH HN
O
OH
H 2N
O
H
N
O
OH
N
O
OH
PCU-lactim
PCU-lactam
O
OH
H 3 C NH
O
O
PCU-lactone
Objectives
 MD simulation
 Binding free energy calculations
 DFT study
Binding free energy calculations
Software: Amber12
Method: MMPB(GB)SA
PCU- peptide inhibitor inside the active site
of South African HIV protease
PCU-peptide inhibitor docked to
HIV protease
MM-PB(GB)SA binding free energy calculations
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.
Binding free energies and its components for the
PCU-models complexed with the HIV protease
HN
H3C
OH
N
O
HN
H3C
OH
HN
O
OH
PCU-lactim
O
OH
H3C NH
O
PCU-lactam
O
O
PCU-lactone
ΔESOL(
ΔESOL(G
ΔGbind(PB ΔGbind(GBS
PB)
B)
SA)
A)
ΔEELE
ΔEVDW
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
PCU-models
Binding free energies and its components for the
PCU-peptides complexed with the HIV protease
OH
OH
O
HN
OH
NH
O
NH
O
NH HN
H2N
O
OH
HN
O O
O
O
O
H 2N
OH
PCU-Lactam-NH-EAIS
NH HN
O
OH
O
O
O
PCU-Lactone-CO-EAIS
IC50= 0.076 µM
PCU-peptides
H
N
O
IC50= 0.850 µM
ΔEELE ΔEVDW
ΔESOL( ΔESOL(G ΔGbind(PB ΔGbind(G
PB)
B)
SA)
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
-29.39
-68.41
52.81
53.46
-69.79
-61.74
PCU-lactone-CO-EAIS(b)
Binding free energies and its components for the
synthesized PCU-peptides complexed with the HIV
protease
OH
O
OH
O
O
OH
NH HN
O
H2N
H
N
NH HN
HN
O
NH
O
O
OH
O
O O
O
O
NH HN
O O
OH
H2N
PCU-Lactam-CO-EAIS
OH
PCU-Lactone-NH-EAIS
PCU-peptides
ΔEELE
ΔEVDW
PCU-lactam-CO-EAIS(a)
-23.21
PCU-lactam-CO-EAIS(b)
ΔESOL( ΔESOL(G
ΔGbind(P
ΔGbind(
PB)
B)
BSA)
GBSA)
-74. 82
117.34
106.88
-87.89
-58.79
-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
-9.01
-74.08
52.55
34.55
-78.71
-57.10
PCU-lactone-NH-EAIS(b)
DFT study of PCU-models
Software: Gaussian09
Method: B3LYP
Basis set: 6-311G**
HN
H3C
OH
N
O
OH
PCU-lactim
HN
H3C
OH
HN
O
O
PCU-lactam
O
OH
H3C NH
O
O
PCU-lactone
Electronic structure properties
Polarizability
NBO Analysis
(HOMO- LUMO) Natural atomic charges
Electrostatic Potential Map
Natural atomic charges (a.u.) on nitrogen and oxygen
nuclei of PCU-models
4
HN
O
5
HN
1
OH
3
O
5
O
2
PCU-lactam
5
O
4
HN
N
1
OH
3
OH
2
PCU-lactim
NH
4
O
1
OH
3
O
2
PCU-lactone
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
Electrostatic Potential Map
PCU-lactam
PCU-lactim
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
(Å3)
µ (Debye)
∆GSolv
PCU-models
α
PCU-lactam
81.218
6.4726
-17.925
PCU-lactim
81.663
3.5616
-17.085
PCU-lactone
79.324
1.2617
-8.893
(kcal/mol)
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