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Structural chemometrics applied to bioactive conformation
of some lignans
Ferreira M. M. C. and Kiralj R.
Universidade Estadual de Campinas - Campinas SP
Resumo [Abstract]
Lignans are natural products that are produced by
various plants and some lower organisms. These compounds
have in-
teresting biological properties like
antitumoral, antiviral, antifungal, antimalarial,
antimitotic, antiinflamatory and other
pharmacologically important activities.
(-)-Hinoquinine is a lignan with g-butyrolactone
as the central ring and two
methylenephenyl groups as substituents. Recently,
its potential activity against Chaga’s disease and
conformational pro-
perties, were studied [1]. Computational approach
to find the bioactive conformation of this compound
resulted in four
stable conformer types with respect to the relative position
of the phenyl rings and approximate molecular symmetry: p…p
stacked (parallel rings), T-shaped
(at high angle to mutually orthogonal rings), extended (no
contact between the rings)
and intermediate (between T-shaped and extended).
Using structural databases and applying structural chemometrics
on
geometry parameters of retrieved structures
as well as of computed conformers was useful
to solve the doubt which
conformation type corresponded to bioactive conformation.
The search for g-butyrolactones
and tetrahydrofurans with
methylenephenyl substituents was performed in the
Cambridge Structural Database CSD) [2] in order
to see conformer
type distribution of the hinoquine-like systems. Four
predominant conformers, the same as in case of (-)-hinoquinine, were
detected with no preference for any conformation type.
This confirms predominant influence of substituents in
the basic
structure as well as of intermolecular interactions (crystal
packing effects). Crystal violet, a standard used in
lignan bioas-
says [2], as well its derivative malachite green, have
been found by systematic search in the Protein Data Bank
[3]. The
only structures contain protein QacR complexed
with these ligands. The bioactive conformation of the ligands
served to
identify the conformation type of (-)-hinoquine that
may be bioactive. Structural parameters that determine
conformation
type were defined and measured. The parameters
included distances between the ring centroids, angles formed
by these
centroids and their sum, the angles between the ring
planes, and the 3D Wiener index of the basic structure.
Phenyl rings
and the 5-membered central ring were considered
as the only rings in this analysis. Principal Component
Analysis and
Hierarchical Cluster Analysis applied to
the geometry parameters of the ligand structures and
the four structures of the
(-)-hinoquine conformers identified the T-shaped as the
potential bioactive conformer. Superposition of this and the crystal
violet conformer confirmed the observation.
Agradecimentos [Acknowledgement]
FAPESP
Referências [References]
1. P. M. Donate, S. Albuquerque, M. M. C. Ferreira, R.
Kiralj et al., in preparation
2. F. H. Allen, Acta Cryst. B58, 380 (2002)
3. H. M. Berman et al., Nucl. Acids Res. 28, 235 (2000)
http://www.rcsb.org/pdb/
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