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Different methodological approaches to the conformational analysis in aroylpyrrolacetic derivatives with antiinflammatory activity
finite size at a finite distance from the spherical objects it illuminates. With this mode1 and the straightforward application of geometry, we have derived a set of equations for shadow generation that are integrated easily into a z-buffer hidden surface algorithm. As implemented, it is capable of handling any number of light sources of varying sizes, at varying finite distances and varying locations. A sample image generated with this algorithm is shown below. Note the complex perceptual detail that only soft shadows can provide. Note also, that the use of specular highlights enhances the visualization of the light source position, and that the addition of a shadowed backplane strengthens the perception of the molecule’s spatial presence. Rendering time comparisons against current methods reveal a significant speed boost. Most molecules tested are drawn about a factor of five times faster. In addition, aliasing artifacts that plague other z-buffer implementations are nonexistent because of the soft shadows’ analytical representation.
STRUCTURE-ACTIVITY RELATIONSHIP BETWEEN THE 3D DISTRIBUTION OF THE ELECTROPHILICITY OF SUGAR DERIVATIVES AND THEIR CYTOTOXIC AND ANTIVIRAL PROPERTIES
DIFFERENT METHODOLOGICAL APPROACHES TO THE CONFORMATIONAL ANALYSIS IN AROYLPYRROLACETIC DERIVATIVES WITH ANTIINFLAMMATORY ACTIVITY R. Pouplana, I.J. Vazquez, and A. Perez Unitat de Fisicoquimica, Departament de Farmacia, versitat de Barcelona, Barcelona, Spain
Uni-
This study is intended to establish the possible active conformations in these chemicals in order to study the electronic features of these geometries and attempt to find out some quantitative relationships explaining their biological activity, as well as to test different conformational methods, underlining their advantages and disadvantages. The conformational methods used were molecular mechanics (CVFF-convergence valence force field), quantum mechanics (AM1 and PM3 semiempirical molecular orbital methods), and finally molecular dynamics. We have studied four different patterns, 2-[ 1,4-dimethyl-5-( l-methylpyrrol-2-yl)carbonyl-lH-pyrrolelacetic acid, 5-benzoyl1,4-dimethylpyrrole-2-acetic acid, 5-benzoyl-l-methylpyrrole-2-acetic acid, and 5-benzoyl-1,2-dihydro-3H-pyrrolo[ 1,2,-alpyrrole- l-acetic acid. The results obtained showed that the maximum number of minima were found using molecular mechanics, whereas quantum mechanics did not reveal all possible geometries that minimize the molecular energy. The molecular mechanics conformational maps pointed out the largest energetic distinction between stable and unstable geometries.
A. Ricca,*t J. Weber,? and J.M.J. Tronchet* *Department of Pharmaceutical Chemistry and TDepartment of Physical Chemistry, University of Geneva, Sciences II, Geneva, Switzerland The cytotoxic activities of a series of sugar derivatives bearing electrophilic groups (1-cyanovinyl, 4-cyanochromen-2-yl and 3-nitrochromen-2-yl) have been correlated with their electrophilic properties. To this end, an electrophilic index was defined as an isovalue surface where the interaction energy with an incoming mode1 nucleophile (HP) was equal to a predefined value. This index, calculated from extended Htickel wave functions, allows one to quantify the electrophilic character of the substrates and to describe its spatial localization within the molecular volume (at Michael acceptor sites, or on other parts of the molecules). Only sugars for which Michael acceptor reactivity was predicted were retained, and they were subdivided into two groups: those showing antivirial activity against a retrovirus and those devoid of such activity. Under these conditions, good correlations between cytotoxic activity and electrophilic reactivity-positive for the first group, and negative for the second-were found. In addition, the ratio of the electrophilicity to the sum of the absolute value of the dipole plus its projection along the principal axis of inertia 2 of the molecule allows one to predict to which of these groups a sugar derivative belongs.
CVFF-Conformational map of 2-[1,4-dimethyl5-(1 -methylpyrrol-2-yl)carbonyl-I H-pyrrolelacetic acid
J. Mol. Graphics,
1994, Vol. 12, March
63
ELECTROSTATIIC STUDY OF THE MODE OF INACTIVATION OF NSAII-JS fN THE ~~H-~~~THA~~ J.J. Lozano, M, Lopez, J. Ruiz, A. Perez, M. Gomara, and R. Pouplana Unitat de Fisico-Quimica, Departament de Farmacia, Universitat de Barcelona, Barcelona, Spain
AM1 -conforma~ionnl map of 2-[1,4-dimethyl5-(1-methylpyrrol-2-yl)~~rbonyl-IH-pyrroie]acetic acid
In an attempt to learn the electrostatic requirements far the differents types of inactivatioil of PGH-synthase,’ the molecular electrostatic potentials (MEPs) of indomethacin and other NSAIDS (me~lofenam~~ acid, flufenamic acid, naproxen, ~urbiprofen~, and MEPS of PGG2 and PGWZ were caIcufated by means of the program’ MGPETE. This program uses MNDO-derived molecular electrostatic potentials, and MEP minima values also may be calculated.3 Previously, a conformational analysis of all structures to be studied was made, starting with the geometries obtained by X-ray diffraction using the semiempirical method AM1 .’ The results were adapted for a visuahzation in a molecular graphics program, ALCHEMY II,5 and the potentials were illustrated by color coding of the surfaces. The MEPS of the indomethacin and PGs have a certain similarity with respect to the distances of the minimums, and it is possible that indomethacin competes with the substrate for binding to the active site. The MEPS of the irreversible inhibitors (ilz vitro) meclofenamic acid and flurbiprofen show a marked minima around the second ring near the halogens atoms, this could explain a reactivity in this zone versus PGH-synthase catnlysis. The values of these minima are greater than the corresponding minima in the carbonyl moiety of the indomethatin compound.
~M3-~onform~t~o~~~ map of 2-fl,4-dimethyl5-(1-methylpyrrol-2-yl)carbonyE-IHrro~e~~cet~~ acid
We remark that the correct way to do a conformational analysis in aroylpyrrolacetic compounds is usingmaleculsr mechanics,and if you need to study the electronic properties of the molecule, you must use a quantum mechanical method constraining the dihedral angles to the molecular mechanics values.
64
J. Mel, Graphics,
1994,
Vol. 12, March
Figure. MEP of indomethacin: red dots, -30 kcallmol to -I5 kcalfmol; yellow dots, -1.5 kcalfmol to 0 kcallmol.
STRUCTURE-ACTIVITY RELATIONSHIP BETWEEN THE 3D DISTRIBUTION OF THE ELECTROPHILICITY OF SUGAR DERIVATIVES AND THEIR CYTOTOXIC AND ANTIVIRAL PROPERTIES
DIFFERENT METHODOLOGICAL APPROACHES TO THE CONFORMATIONAL ANALYSIS IN AROYLPYRROLACETIC DERIVATIVES WITH ANTIINFLAMMATORY ACTIVITY R. Pouplana, I.J. Vazquez, and A. Perez Unitat de Fisicoquimica, Departament de Farmacia, versitat de Barcelona, Barcelona, Spain
Uni-
This study is intended to establish the possible active conformations in these chemicals in order to study the electronic features of these geometries and attempt to find out some quantitative relationships explaining their biological activity, as well as to test different conformational methods, underlining their advantages and disadvantages. The conformational methods used were molecular mechanics (CVFF-convergence valence force field), quantum mechanics (AM1 and PM3 semiempirical molecular orbital methods), and finally molecular dynamics. We have studied four different patterns, 2-[ 1,4-dimethyl-5-( l-methylpyrrol-2-yl)carbonyl-lH-pyrrolelacetic acid, 5-benzoyl1,4-dimethylpyrrole-2-acetic acid, 5-benzoyl-l-methylpyrrole-2-acetic acid, and 5-benzoyl-1,2-dihydro-3H-pyrrolo[ 1,2,-alpyrrole- l-acetic acid. The results obtained showed that the maximum number of minima were found using molecular mechanics, whereas quantum mechanics did not reveal all possible geometries that minimize the molecular energy. The molecular mechanics conformational maps pointed out the largest energetic distinction between stable and unstable geometries.
A. Ricca,*t J. Weber,? and J.M.J. Tronchet* *Department of Pharmaceutical Chemistry and TDepartment of Physical Chemistry, University of Geneva, Sciences II, Geneva, Switzerland The cytotoxic activities of a series of sugar derivatives bearing electrophilic groups (1-cyanovinyl, 4-cyanochromen-2-yl and 3-nitrochromen-2-yl) have been correlated with their electrophilic properties. To this end, an electrophilic index was defined as an isovalue surface where the interaction energy with an incoming mode1 nucleophile (HP) was equal to a predefined value. This index, calculated from extended Htickel wave functions, allows one to quantify the electrophilic character of the substrates and to describe its spatial localization within the molecular volume (at Michael acceptor sites, or on other parts of the molecules). Only sugars for which Michael acceptor reactivity was predicted were retained, and they were subdivided into two groups: those showing antivirial activity against a retrovirus and those devoid of such activity. Under these conditions, good correlations between cytotoxic activity and electrophilic reactivity-positive for the first group, and negative for the second-were found. In addition, the ratio of the electrophilicity to the sum of the absolute value of the dipole plus its projection along the principal axis of inertia 2 of the molecule allows one to predict to which of these groups a sugar derivative belongs.
CVFF-Conformational map of 2-[1,4-dimethyl5-(1 -methylpyrrol-2-yl)carbonyl-I H-pyrrolelacetic acid
J. Mol. Graphics,
1994, Vol. 12, March
63
ELECTROSTATIIC STUDY OF THE MODE OF INACTIVATION OF NSAII-JS fN THE ~~H-~~~THA~~ J.J. Lozano, M, Lopez, J. Ruiz, A. Perez, M. Gomara, and R. Pouplana Unitat de Fisico-Quimica, Departament de Farmacia, Universitat de Barcelona, Barcelona, Spain
AM1 -conforma~ionnl map of 2-[1,4-dimethyl5-(1-methylpyrrol-2-yl)~~rbonyl-IH-pyrroie]acetic acid
In an attempt to learn the electrostatic requirements far the differents types of inactivatioil of PGH-synthase,’ the molecular electrostatic potentials (MEPs) of indomethacin and other NSAIDS (me~lofenam~~ acid, flufenamic acid, naproxen, ~urbiprofen~, and MEPS of PGG2 and PGWZ were caIcufated by means of the program’ MGPETE. This program uses MNDO-derived molecular electrostatic potentials, and MEP minima values also may be calculated.3 Previously, a conformational analysis of all structures to be studied was made, starting with the geometries obtained by X-ray diffraction using the semiempirical method AM1 .’ The results were adapted for a visuahzation in a molecular graphics program, ALCHEMY II,5 and the potentials were illustrated by color coding of the surfaces. The MEPS of the indomethacin and PGs have a certain similarity with respect to the distances of the minimums, and it is possible that indomethacin competes with the substrate for binding to the active site. The MEPS of the irreversible inhibitors (ilz vitro) meclofenamic acid and flurbiprofen show a marked minima around the second ring near the halogens atoms, this could explain a reactivity in this zone versus PGH-synthase catnlysis. The values of these minima are greater than the corresponding minima in the carbonyl moiety of the indomethatin compound.
~M3-~onform~t~o~~~ map of 2-fl,4-dimethyl5-(1-methylpyrrol-2-yl)carbonyE-IHrro~e~~cet~~ acid
We remark that the correct way to do a conformational analysis in aroylpyrrolacetic compounds is usingmaleculsr mechanics,and if you need to study the electronic properties of the molecule, you must use a quantum mechanical method constraining the dihedral angles to the molecular mechanics values.
64
J. Mel, Graphics,
1994,
Vol. 12, March
Figure. MEP of indomethacin: red dots, -30 kcallmol to -I5 kcalfmol; yellow dots, -1.5 kcalfmol to 0 kcallmol.