Biology Reference
In-Depth Information
18.6 Structure-Activity Studies of Porphyric
Insecticide Modulators
The identification of a significant number of chemicals exhibiting insecticidal activity
encouraged detailed structure-function analyses of these modulators. Accordingly
structure-function studies of modulators belonging to the Oph, Dpy, pyridinium,
oxypyridine, pyrrole and 8-hydroxyquinoline templates were investigated. The chem-
ical structures of the selected modulators and their template affiliation are depicted
below in Figs. 18.5 , 18.6 and 18.7 .
Quantitative structure activity relationship (QSAR) analysis was performed on a
Digital Equipment Co. workstation Model 3520, operating on a VMS platform.
Chem-X software, (Chemical Design Limited, Oxford, England) was used to build
3-dimensional chemical structures and to carry out QSAR analysis. The latter
involved, among other things: (a) optimization of the chemical structures via Mopac
(QCPE, version 5, 1989) using MNDO or PM1 Hamiltonians, (b) writing the
optimized structures of Oph and its analog to a database, (c) calculation of 24 different
electronic and physical organic properties for each structure, i.e. descriptors,
(d) correlation analysis between the 24 descriptors and biological activity, and
(e) stepwise multiple regression analysis to determine the nature of relationships
between biological activity and various descriptors.
Calculation of electrostatic potential energy levels at various sites of a given
molecule was performed using Chem-X software. Chem-X treats the charge on
each atom in a molecule as a point charge positioned at the center of the atom. A
positive unit charge equivalent to that of a proton is placed at each grid point and the
electrostatic interaction between groups of atoms and the unit charge is calculated.
The number of grid points used in the calculation, one point per Angstrom in this
case, is usually set by the operator. After calculations were completed, electrostatic
isopotential contour lines were drawn. The level of potential energy in kcal per
mole was also selected by the operator. We chose values of 10 kcal/mol for positive
potential energy levels and
10 kcal/mol for negative potential energy levels. Since
the interaction of a positive probe with a positive region of the molecule generated
positive energy levels they were interpreted as repelling. Likewise since the inter-
action of a positive charge probe with a negative region of the molecule generated
negative energy levels they were interpreted as binding or attracting energy levels.
In this manner the attraction or repulsion at various loci of a particular molecule
toward a positive charge was well defined by the negative and positive potential
energy contour lines respectively, which in fact delineated positive charge binding
or repelling electrostatic volumes surrounding various sections of a molecule.
Quantitative and positional differences between the electrostatic fields of various
modulators were calculated by determining the exclusive positive charge binding
and repelling volumes for each analog in comparison to a reference molecule. The
calculation of exclusive volumes (i.e. non overlapping volumes between any two
molecules) was achieved via a Chem-X software module that calculated exclusive
electrostatic field volumes for pairs of molecules from the electrostatic volumes of
each individual molecule. In so doing it became possible to compare quantitative
and qualitative positional differences between various analogs within each template.
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