Page 129 - Chiral Separation Techniques

106 4 CHIRBASE: Database Current Status and Derived Research Applications using …

4.5 3D Structure Database Searches

Today, 3D databases, which provide the means for storing and searching for 3D
information of compounds, are proven to be useful tools in drug discovery programs.
This is well exemplified with the recent discovery of novel nonpeptide HIV-1 pro-
tease inhibitors using pharmacophore searches of the National Cancer Institute 3D
structural database [13–15].
In 3D searching strategies, the relevant molecules will be found by searching the
fitting 3-D molecular properties around the chirality center instead of similar func-
tional groups, as it can be searched using 2D query structures. The facilities of
ISIS/3D fulfil this ability to import and search 3D structures in CHIRBASE. The 3D
structures were built with the program CORINA developed by Gasteiger’s group
[16] and included in TSAR [17], a fully integrated quantitative structure-activity
relationship (QSAR) package. For each 2D structure, only a single conformation
was stored in CHIRBASE because ISIS/3D allows conformationally flexible sub-
structure (CFS) searching [18]. In a CFS search, the conformational fitting is the
process of rotating single bonds in 3D structures to fit the constraints of the query.
Actually, searching a database of flexible conformations is quite efficient and does
not require the storage of accurate models as produced from X-ray crystallographic
data, as long as we always build the database with models derived from the same
force field calculations and therefore control the errors.
A very interesting approach in the prediction of a chiral resolution is the study of
the solute binding to the stationary phase receptor. This habitually requires the uti-
lization of sophisticated docking and molecular dynamics techniques, and much
computer time. However, numerous reasonable predictions of CSP-solute binding
have been made in the literature simply by specifying the spatial arrangement of a
small number of atoms or functional groups [19]. Here, we will call such an arrange-
ment “enantiophore”. A key concept of CHIRBASE 3D searches is to find molecules
from a 3D query of a compound reduced to a description of the chemical environ-
ment that corresponds to the enantiophore hypothesis. This new approach now per-
mits us to consider the molecules in terms of interaction centers of the solute and the
geometric relationship between those centers. For example, an “enantiophore” may
be defined by three atoms separated by a set of distances with some tolerances (usu-
ally 0.5 A). Then a search in ISIS/3D will find only the structures that satisfy the
enantiophore query. In this work, we will explore two kinds of strategies.

4.5.1 Queries Based on CSP Receptor

The enantiophore query used in the search is derived from the CSP and directly built
from a 3D structure model of the target CSP molecule, as it can be used today for
the determination of new lead compounds [20, 21]. This procedure does not need an
important modeling expertise. One can easily recognize the different center types in
the receptor in question. These can be hydrogen-bond donors and acceptors, charged