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Applications of quantum chemical methods to drug design problems
O$ ,/p / - \C”
-0
2
__p’
P*O‘O-
2 Several crystal structures have been determined for salts of the monoanion of (1). The cyclohexylammonium salt (D. G. Watson & 0. Kennard, Actu Cryst. 1973, B29, 2358) was chosen for optimization of the geometry of the anion with MM2. Torsional strain proved to be the dominant term in the total steric energy expression, and to relieve it the angle between carboxyl and C=C-0 planes increased from cu. 7” in the crystal to >80” through twisting about Cl-C2. Similar treatment of a model for (2) yielded less strain and lower energy. Subsequently the crystal structure of the tri(cyclohexylammonium) salt of (2) was determined in our laboratory. The pyruvate moiety was found to be relatively flat, with a 5” angle between carboxyl and O=C-C planes; but upon optimization of the trianion using AMPAC with MNDO parameters the carboxyl group rotated to near perpendicularity. The C-C-C-P torsion angle increased from 106” to 141”, thereby moving the two sites of negative charge farther apart. When the starting conformation was given a 1” angle between the planes, the planar geometry persisted but the final heat of formation was 5.4 kcal/mol less negative. Similar optimizations of the trianions of (1) constructed from crystal data for the monoanion yielded both perpendicular and parallel carboxyl groups, but the former conformations are 6.4 kcal/mol more stable. Ab initio calculation of the energies with the STO-3G basis set gives a preference for the perpendicular orientation by 2.2 kcal/mol in (1) and 2.1 kcal/mol in (2). Thus the planar conformation of (1) considered previously (D. M. Hayes, G. L. Kenyon and P. A. Kollman, J. Am. Chem. Sot. 1978, 100, 4331) did not represent quite the minimum energy in STO-3G. With this basis set the energy change upon isomerization of (1) to (2) is +4.6 kcal/mol, or +4.5 kcal/mol based upon planar geometry. Solvation effects will be very large for such trianions, but in view of the very similar molecular dimensions and almost identical van der Waals volumes for (1) and (2) they are expected to be similar for both species. Thus one may correlate Gibbs free energies with E values and predict that cu. 2400 molecules of (1) will exist for every one of (2) at 298 K.
Molecular determinants ognition and activation
of benzodiazepine
receptor rec-
properties which modulate receptor binding affinities and types of activities and from them to develop a consistent model of receptor recognition and activation. Experimentally, the affinities of these analogs for this receptor and the nature and potency of the activity, agonist (anticonvulsant), antagonist or inverse agonist (proconvulsant/convulsant) were determined. Theoretically, molecular orbital calculations were carried out for all analogs, using semiempirical quantum mechanical methods. In addition to the optimization of structures, a number of electronic properties such as polarizations, partition coefficients, proton and electron affinities were computed and examined for their ability to modulate relative affinities and modes of activation of the receptor. From these studies, a model for receptor recognition involving two anchoring hydrogen-bond accepting sites, and for activation involving charge transfer interactions between the most lipophilic aromatic ring and the receptor were deduced. These hypothesis could systematically account for the three different types of behavior: agonist, antagonist and inverse agonist, observed for these analogs. Finally, by complementarity, some steric and electronic characteristics of the receptor binding site could be deduced.
Applications of quantum sign problems
H. P. Weber, C. Ehrhardt and Ph. Floersheim Preclinical Research Pharma, SANDOZ AG Basel, Switzerland A useful Structure Activity Relationship-the basis of a rational Drug Design-requires a set of selected structural and electronic parameters which correlates, or explains, the biological activity of a set of drug molecules. While structural parameters (e.g., interatomic distances, molecular shape, etc.) can be obtained via Molecular Mechanics and Graphics quite readily for biologically relevant molecular systems comprising up to some thousand atoms, electronic parameters have to be obtained, in praxi, from small model systems of usually some ten atoms if rigorous MO methods are applied, or some hundred atoms in semi-empirical calculations. The application of Quantum Chemical methods on model systems as used in practical drug design work will be discussed and illustrated with two examples: (1)
In the study of the interaction of groove binding drug molecules with DNA, the geometry of H-bonds to the phosphate group had to be investigated. Both a survey of the experimental data available from the Cambridge Crystal Data Base, and a theoretical study of the model system H-O
Hugo Villar and Gilda Loew Molecular Research Institute, Alto, California, USA
Palo
Computational and pharmacological studies have been made of 15 compounds from five different chemical families known to bind to the GABAa/Benzodiazipine receptor. The goal of these studies was to identify and calculate molecular
60
J. Mol. Graphics,
0 \
845 Page Mill Road,
1990, Vol. 8, March
chemical methods to drug de-
P / H-O
. . . . . H -0 \
/
B \ 0
by GAUSSIAN86 MO calculations with various basis sets have been done. The results will be discussed and its application demonstrated.
(2)
In the course of a study of serine proteases we started a theoretical investigation of the interaction of boronic acid with a methanol molecule. The starting model was extracted from the crystal structure of the alphachymotrypsin-phenylethyl boronic acid complex (A. Tulinsky and R. A. Blevins, J. Biol. Chem. 1987, 262, pp 7737):
OH
B /
/ Me-B..
. \
.
.O \
OH
CA3
The boron atom in this complex is in a tetrahedral configuration. Results and conclusions will be discussed.
J. Mol. Graphics,
1990, Vol. 8, March
61
-0
2
__p’
P*O‘O-
2 Several crystal structures have been determined for salts of the monoanion of (1). The cyclohexylammonium salt (D. G. Watson & 0. Kennard, Actu Cryst. 1973, B29, 2358) was chosen for optimization of the geometry of the anion with MM2. Torsional strain proved to be the dominant term in the total steric energy expression, and to relieve it the angle between carboxyl and C=C-0 planes increased from cu. 7” in the crystal to >80” through twisting about Cl-C2. Similar treatment of a model for (2) yielded less strain and lower energy. Subsequently the crystal structure of the tri(cyclohexylammonium) salt of (2) was determined in our laboratory. The pyruvate moiety was found to be relatively flat, with a 5” angle between carboxyl and O=C-C planes; but upon optimization of the trianion using AMPAC with MNDO parameters the carboxyl group rotated to near perpendicularity. The C-C-C-P torsion angle increased from 106” to 141”, thereby moving the two sites of negative charge farther apart. When the starting conformation was given a 1” angle between the planes, the planar geometry persisted but the final heat of formation was 5.4 kcal/mol less negative. Similar optimizations of the trianions of (1) constructed from crystal data for the monoanion yielded both perpendicular and parallel carboxyl groups, but the former conformations are 6.4 kcal/mol more stable. Ab initio calculation of the energies with the STO-3G basis set gives a preference for the perpendicular orientation by 2.2 kcal/mol in (1) and 2.1 kcal/mol in (2). Thus the planar conformation of (1) considered previously (D. M. Hayes, G. L. Kenyon and P. A. Kollman, J. Am. Chem. Sot. 1978, 100, 4331) did not represent quite the minimum energy in STO-3G. With this basis set the energy change upon isomerization of (1) to (2) is +4.6 kcal/mol, or +4.5 kcal/mol based upon planar geometry. Solvation effects will be very large for such trianions, but in view of the very similar molecular dimensions and almost identical van der Waals volumes for (1) and (2) they are expected to be similar for both species. Thus one may correlate Gibbs free energies with E values and predict that cu. 2400 molecules of (1) will exist for every one of (2) at 298 K.
Molecular determinants ognition and activation
of benzodiazepine
receptor rec-
properties which modulate receptor binding affinities and types of activities and from them to develop a consistent model of receptor recognition and activation. Experimentally, the affinities of these analogs for this receptor and the nature and potency of the activity, agonist (anticonvulsant), antagonist or inverse agonist (proconvulsant/convulsant) were determined. Theoretically, molecular orbital calculations were carried out for all analogs, using semiempirical quantum mechanical methods. In addition to the optimization of structures, a number of electronic properties such as polarizations, partition coefficients, proton and electron affinities were computed and examined for their ability to modulate relative affinities and modes of activation of the receptor. From these studies, a model for receptor recognition involving two anchoring hydrogen-bond accepting sites, and for activation involving charge transfer interactions between the most lipophilic aromatic ring and the receptor were deduced. These hypothesis could systematically account for the three different types of behavior: agonist, antagonist and inverse agonist, observed for these analogs. Finally, by complementarity, some steric and electronic characteristics of the receptor binding site could be deduced.
Applications of quantum sign problems
H. P. Weber, C. Ehrhardt and Ph. Floersheim Preclinical Research Pharma, SANDOZ AG Basel, Switzerland A useful Structure Activity Relationship-the basis of a rational Drug Design-requires a set of selected structural and electronic parameters which correlates, or explains, the biological activity of a set of drug molecules. While structural parameters (e.g., interatomic distances, molecular shape, etc.) can be obtained via Molecular Mechanics and Graphics quite readily for biologically relevant molecular systems comprising up to some thousand atoms, electronic parameters have to be obtained, in praxi, from small model systems of usually some ten atoms if rigorous MO methods are applied, or some hundred atoms in semi-empirical calculations. The application of Quantum Chemical methods on model systems as used in practical drug design work will be discussed and illustrated with two examples: (1)
In the study of the interaction of groove binding drug molecules with DNA, the geometry of H-bonds to the phosphate group had to be investigated. Both a survey of the experimental data available from the Cambridge Crystal Data Base, and a theoretical study of the model system H-O
Hugo Villar and Gilda Loew Molecular Research Institute, Alto, California, USA
Palo
Computational and pharmacological studies have been made of 15 compounds from five different chemical families known to bind to the GABAa/Benzodiazipine receptor. The goal of these studies was to identify and calculate molecular
60
J. Mol. Graphics,
0 \
845 Page Mill Road,
1990, Vol. 8, March
chemical methods to drug de-
P / H-O
. . . . . H -0 \
/
B \ 0
by GAUSSIAN86 MO calculations with various basis sets have been done. The results will be discussed and its application demonstrated.
(2)
In the course of a study of serine proteases we started a theoretical investigation of the interaction of boronic acid with a methanol molecule. The starting model was extracted from the crystal structure of the alphachymotrypsin-phenylethyl boronic acid complex (A. Tulinsky and R. A. Blevins, J. Biol. Chem. 1987, 262, pp 7737):
OH
B /
/ Me-B..
. \
.
.O \
OH
CA3
The boron atom in this complex is in a tetrahedral configuration. Results and conclusions will be discussed.
J. Mol. Graphics,
1990, Vol. 8, March
61