Molecular Modeling Studies of Semi–synthetic

Molecular Modeling Studies of Semi–synthetic

Brazilian Chemical Society (SBQ). Division of Medicinal Chemistry. 4th Brazilian Symposium on Medicinal Chemistry
Molecular Modeling Studies
Alzheimer prototypes
1*
2
of
Semi–synthetic
1
3
3
piperidine
4
anti–
5
Danuello, A. ; Romeiro, N. C. ; Pivatto, M. ; Giesel, G. ; Verli, H. ; Castro, N. G. ; Viegas Jr., C. ;
2
2
1
Barreiro, E. J. ; Fraga, C. A. M. ; Bolzani, V. S.
[email protected]
1
Núcleo de Bioensaios, Biossíntese e Ecofisiologia de Produtos Naturais (NuBBE), Instituto de Química,
UNESP, Araraquara, Brazil
2
Laboratório de Avaliacão e Síntese de Substâncias Bioativas (LASSBio®), Faculdade de Farmácia, UFRJ,
Rio de Janeiro, Brazil
3
Faculdade de Farmácia – Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
4
Departamento de Farmacologia Básica e Clínica, UFRJ, Rio de Janeiro, Brazil
5
LFQM Laboratório de Fitoquímica e Química Medicinal, UNIFAL-MG, Alfenas, Brazil
Keywords: acetylcholinesterase inhibitors; molecular docking; molecular dynamics; (–)-spectaline; (–)-cassine.
Introduction
Recently, leaves and flowers of Senna spectabilis
were reported to be valuable sources of bioactive
piperidine alkaloids. Electrospray ionization mass
spectrometry analysis of an extract from this plant
showed alkaloids that coexist as a mixture of
homologous substances, identified as (–)-cassine (1)
and (–)-spectaline (2), which differ in the size of the
1
side chain at C-6 (Figure 1). Our recent
investigation has shown that the mixture of the semisynthetic derivatives (–)-3-O-acetyl-cassine (3,
LASSBio-767A) and (–)-3-O-acetyl-spectaline (4,
LASSBio-767B) are potent cholinergic agents in vivo,
with a unique profile, combining noncompetitive
cholinesterase inhibition and CNS selectivity, with a
2
few peripheral side effects.
HO
O
H 3C
N
H
n
1: n = 4, (-)-cassine
2: n = 6, (-)-spectaline
H 3C
CH3
O
O
H 3C
O
N
H
n
CH3
3: n = 4, LASSBio-767A
4: n = 6, LASSBio-767 B
Figure 1. Alkaloids and semi-synthetic derivatives
from S. spectabilis
Taking into account these findings, we have
investigated the recognition pattern of the alkaloids
3, 4 by the active site of the enzyme AChE, through
the molecular modeling studies, and the structure of
Torpedo californica acetylcholinesterase (TcAChE)
in complex with known inhibitors, exploiting flexible
docking methodology. Finally, molecular dynamics
studies of these compounds have been performed,
aiming at a more profound understanding of the
hypothetic interactions with AChE.
Results and Discussion
After protein and ligands preparations, docking
with FlexE was performed, using the default FlexX
scoring function. Flexible docking has shown
different binding conformations and interaction
patterns between these two compounds and AChE,
especially in the peripheral anionic site (Figure 2).
Figure 2. Top scored ligand-tcAChE complexes
obtained by flexible docking with FlexE for 3 (A) and
4 (B).
In order to obtain further information regarding
these compounds’ dynamics upon AChE inhibition,
the complexes between the enzyme and LASSBio767A or LASSBio-767B were submitted to molecular
dynamics (MD) simulations in explicit water solvent.
Both compounds show significant reorientations in
the simulated time scale, indicating an important role
of solvent on the complex flexibility and stabilization.
However, such conformational accommodation does
not appear to induce any further modification in the
protein secondary structure elements.
Conclusions
Flexible docking and molecular dynamics studies
indicated LASSBio-767A (3) as the most active
compound, which presents both more favorable
interaction with the target protein and is held with
less intensity by the solvent.
Acknowledgements
____________________
1
Pivatto, M.; Crotti, A. E. M.; Lopes, N. P.; Castro-Gamboa, I.;
Rezende, A.; Viegas Jr., C.; Young, M. C. M.; Furlan, M.; Bolzani, V.
S. J. Braz. Chem. Soc. 2005, 16, 1431.
2
Viegas Jr., C.; Bolzani, V. S.; Pimentel, L. S.; Castro, N. G.; Cabral,
R. F.; Costa, R. S.; Floyd, C.; Rocha, M. S.; Young, M. C.; Barreiro, E.
J.; Fraga, C. A. M. Bioorg. Med. Chem. 2005, 13, 4184.
4th Brazilian Symposium on Medicinal Chemistry – BrazMedChem2008