3.3 Molecular modelling
Fig. 1. shows the superimposition of optimized OA and (R)-OA
structure generated from X-Ray data, this confirms that
CAChe™ system is accurate and promising in predicting
OA-like compounds. This X-ray data and that of chlordimeform were
utilized as the starting point for building the new structures of
target molecules. At first, the geometries of the
energy-minimized molecules were checked using the CAChe 3D
visualization tools and then reoriented to compare the
superimposition of side-chain nitrogen atom and the -atom of phenyl group in
each structure (ref. Fig. 1): as these features have been
postulated to be important for OA activity [20-22]. Some
work in this field can be found in our recent report [23].
Fig. 1. Superimposed X-Ray crystallographic and
computer-generated structure of OA*.
*The dimmed structure is energy-optimized from CACheª
with MM2 and PM3 force fields. The highlighted one is
generated from the X-ray coordinates of (R)-OA
hydrochloride. Hydrogens are omitted for clarity.
SBOs and their thiazoline derivatives SBTs possess
a phenyl group and a side chain which containes two nitrogen
atoms. The distance from the side-chain nitrogen atom to the
oxygen in p-OH at phenyl group of OA(Fig.1) was calculated
and compared with the corresponding distance between the
heterocyclic nitrogen atom to the substituent of phenyl group in SBOs
and SBTs. An example of the oxazoline 29 and its
thiazoline derivative CIT was built, energy-minimized, and
reoriented to give a structure, in which the phenyl and oxazoline
or thiazoline rings are held in a nonplanar conformation by an
amino nitrogen bridge[24] and could be superimposed with OA at
low energy cost (Fig. 2, Table 5). When the nitrogen atoms of OA
and oxazoline ring of 29, and oxygen atom of p-OH
in OA and m-Cl of 29 are overlaid, the formamidine
group of 29 can occupy space similar to the ethylamine
group of OA: 29 possesses a similar nitrogen-to-chlorine
distance (7.25 Å, Fig. 3a) to nitrogen-to-oxygen (7.75 Å, Fig.
3b) of OA. In addition, 29 (Fig. 3a) and OA (Fig. 3b)
showed a similar electrostatic potential compared to CIT
(Fig. 3c)(ref. to electrostatic potential part for details).
Fig. 2. Superimposed computer-generated
fitting structure of a) OA and 29 and b) OA and CIT
(Hydrogens are omitted for clarity)
Fig.2.a
Fig.2.b
Superimposition of energy-minimized OA and 29 revealed
structural and conformational similarities that might account for
the high activity of 29. Energy-minimized CIT is
not superimposed well with OA (Fig. 2b, Table 5): the
nitrogen-to-chlorine distance is 5.41 Å (Fig. 3c), apparently
different from the distance nitrogen-to-oxygen (7.75 Å, Fig. 3b)
of OA. It's noteworthy that oxazoline and thiazoline's
five-membered hetero rings overlay with the side chain of OA in
completely different direction: the oxygen of oxazoline 29
is in the same side where the hydroxyl group exits, while the
sulfer atom in thiazoline CIT is shown to be at the
opposite zone.
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