Biomedical subjects

P L A Popelier

Publications and source records attributed to P L A Popelier.

13 recordsLinked to original sources

PubMed2007

Atom-atom partitioning of total (super)molecular energy: the hidden terms of classical force fields.

Classical force fields describe the interaction between atoms that are bonded or nonbonded via simple potential energy expressions. Their parameters are often determined by fitting to ab initio energies and electrostatic potentials. A direct quantum chemical guide to constructing a force field would be the atom-atom partitioning of the energy of molecules and van der Waals complexes relevant to the force field. The authors used the theory of quantum chemical topology to partition the energy of five systems [H2, CO, H2O, (H2O)2, and (HF)2] in terms of kinetic, Coulomb, and exchange intra-atomic and interatomic contributions. The authors monitored the variation of these contributions with changing bond length or angle. Current force fields focus only on interatomic interaction energies and assume that these purely potential energy terms are the only ones that govern structure and dynamics in atomistic simulations. Here the authors highlight the importance of self-energy terms (kinetic and intra-atomic Coulomb and exchange).

Journal Article↗

PubMed2006

QSAR models based on quantum topological molecular similarity.

A new method called quantum topological molecular similarity (QTMS) was fairly recently proposed [J. Chem. Inf. Comp. Sc., 41, 2001, 764] to construct a variety of medicinal, ecological and physical organic QSAR/QSPRs. QTMS method uses quantum chemical topology (QCT) to define electronic descriptors drawn from modern ab initio wave functions of geometry-optimised molecules. It was shown that the current abundance of computing power can be utilised to inject realistic descriptors into QSAR/QSPRs. In this article we study seven datasets of medicinal interest : the dissociation constants (pK(a)) for a set of substituted imidazolines , the pK(a) of imidazoles , the ability of a set of indole derivatives to displace [(3)H] flunitrazepam from binding to bovine cortical membranes , the influenza inhibition constants for a set of benzimidazoles , the interaction constants for a set of amides and the enzyme liver alcohol dehydrogenase , the natriuretic activity of sulphonamide carbonic anhydrase inhibitors and the toxicity of a series of benzyl alcohols. A partial least square analysis in conjunction with a genetic algorithm delivered excellent models. They are also able to highlight the active site, of the ligand or the molecule whose structure determines the activity. The advantages and limitations of QTMS are discussed.

Alcohol Dehydrogenase↗

PubMed2006

A convergent multipole expansion for 1,3 and 1,4 Coulomb interactions.

Traditionally force fields express 1,3 and 1,4 interactions as bonded terms via potentials that involve valence and torsion angles, respectively. These interactions are not modeled by point charge terms, which are confined to electrostatic interactions between more distant atoms (1,n where n>4). Here we show that both 1,3 and 1,4 interactions can be described on the same footing as 1,n (n>4) interactions by a convergent multipole expansion of the Coulomb energy of the participating atom pairs. The atomic multipole moments are generated by the theory of quantum chemical topology. The procedure to make the multipole expansion convergent is based on a "shift procedure" described in earlier work [L. Joubert and P. L. A. Popelier, Molec. Phys. 100, 3357 (2002)].

Journal Article↗

PubMed2005

The cytotoxicity of ortho alkyl substituted 4-X-phenols: a QSAR based on theoretical bond lengths and electron densities.

A new method called quantum topological molecular similarity (QTMS) was recently proposed [O'Brien, S. E.; Popelier, P. L. A. J. Chem. Inf. Comp. Sci.2001, 41, 764] and has been shown to be successful in a variety of medicinal, ecological and physical organic QSAR/QSPRs. QTMS method uses electronic descriptors drawn from ab initio wavefunctions of geometry-optimized molecules. We investigated a remarkable and unusual set of ortho alkyl-substituted phenols [Selassie, C. D.; Verma, R. P.; Kapur, S.; Shusterman, A. J.; Hansch, C. J. Chem. Soc., Perkin2002, II, 1112], recently studied by the Hansch group. Our results do not support their proposal that a steric factor is important in the determination of the cytotoxicity of this set of substituted phenols. Thus, we conclude that the cytotoxicity of these sterically encumbered phenols is dependent primarily on electronic and radical effects, and that steric issues do not appear to be a critical distinguishing factor.

Alkylation↗

PubMed2005

The electrostatic potential generated by topological atoms. II. Inverse multipole moments.

Quantum chemical topology defines finite atoms, whose bounded electron density generates a well-defined electrostatic potential. A multipole expansion based on spherical tensors provides a potential that is formally convergent outside the divergence sphere. Part I of this series [P. L. A. Popelier and M. Rafat, Chem. Phys. Lett.376, 148 (2003)] showed that a continuous multipole expansion expands the convergence region, thereby allowing the electrostatic potential to be evaluated at short range. Here, we propose a different method, based on "inverse" multipole moments, enabling an expansion that converges everywhere. These moments are defined by inverse (i.e., negative) powers of the magnitude of the position vector describing the electron density inside the atom. We illustrate this technique on nitrogen in N(2), oxygen in H(2)O, and oxygen in the phenolic group of the amino acid tyrosine. The proposed method constitutes a considerable advance over the method presented in Part I.

Journal Article↗

PubMed2005

Quantum chemical topology (QCT) descriptors as substitutes for appropriate Hammett constants.

A technique called quantum topological molecular similarity (QTMS) was recently proposed [J. Chem. Inf. Comput. Sci., 2001, 41, 764] in order to construct a variety of medicinal, ecological and physical organic QSAR/QSPRs, based on modern ab initio wave functions of geometry optimised molecules, in combination with quantum chemical topology (QCT). The current abundance of computing power can be utilised to inject realistic descriptors into QSAR/QSPRs. In previous work [J. Chem. Soc., Perkin Trans. 2, 2002, 1231] it was proven that a set of Hammett constants (sigma(p), sigma(m), sigma(I) and sigma(p)0) for a sizeable set of mono- and polysubstituted carboxylic acids can be replaced by QCT bond descriptors. Using QTMS and proper statistical validation we examined seven data sets in total. The first three sets (para-substituted phenols (sigma-), substituted toluenes (sigma+) and bromophenethylamines (sigma+)) corroborate that a wider class of Hammett constants can also be replaced by QCT descriptors. A fourth set (benzyl radicals) focuses on non-Hammett behaviour being superimposed on Hammett behaviour. QCT descriptors selectively correlate with Hammett behaviour. The QTMS analysis of the last three sets (toxicity of benzyl alcohols, chromatographic capacity factors of chalcones and herbicidal activity of 5-chloro-2,3-dicyanopyrazines) screens for false positives. This test is successfully passed in that QCT descriptors fail when lipophilicity/hydrophobicity is in charge. Hence, overall, the discriminatory capacity of QCT descriptors is established, in detecting Hammett behaviour and specifically replacing the Hammett constants by more modern and non-empirical descriptors.

Journal Article↗

PubMed2005

Rendering of quantum topological atoms and bonds.

In this article, we describe and apply an algorithm that visualizes atoms and bonds in molecules and van der Waals complexes, based on the topology of the electron density. The theory of quantum chemical topology defines both atoms and bonds via a single consistent procedure, and enables the association of an atomic shape with an atomic property (charge, dipole moment, volume, ...). Special attention is paid to the bridging of gaps arising in interatomic surfaces, in the presence of ring critical points or high ellipticity. This algorithm, in conjunction with the graphical user interface of the computer program MORPHY enables robust and efficient rendering of complicated interatomic surfaces, as found in larger systems.

Adamantane↗

PubMed2004

The quantum topological electrostatic potential as a probe for functional group transferability.

The electrostatic potential can be used as an appropriate and convenient indicator of how transferable an atom or functional group is between two molecules. Quantum-chemical topology (QCT) is used to define the electron density of a molecular fragment and the electrostatic potential it generates. The potential generated on a grid by the terminal aldehyde group of the biomolecule retinal is compared with the corresponding aldehyde group in smaller molecules derived from retinal. The terminal amino group in the free amino acid lysine was treated in a similar fashion. Each molecule is geometry-optimized by an ab initio calculation at B3LYP/6-311G+(2d,p)//HF/6-31G(d) level. The amino group in lysine is very little influenced by any part of the molecule further than two C atoms away. However, the aldehyde group in retinal is influenced by molecular fragments six C atoms away. This dramatic disparity is ascribed to the difference in saturation in the carbon chains; retinal contains a conjugated hydrocarbon chain but lysine an aliphatic one.

Aldehydes↗

PubMed2004

Distributed polarizability analysis for para-nitroaniline and meta-nitroaniline: functional group and charge-transfer contributions.

Topological partitioning of electronic properties is used to investigate the polarizability of para-nitroaniline and meta-nitroaniline. The distributed polarizabilities for atoms are combined into total local or generalized distributed contributions for the amino, ring, and nitro functional groups; generalized distributed group contributions have not been calculated before. The local group contributions are transferable between the two molecules only when charge transfer is suppressed, but the generalized distributed contributions prove surprisingly similar in the two molecules, apparently because they treat charge-transfer contributions explicitly.

Journal Article↗

PubMed2004

Estimation of pKa using quantum topological molecular similarity descriptors: application to carboxylic acids, anilines and phenols.

The current availability of cheap computer power enables the construction of QSARs from modern ab initio quantum chemical data. Multivariate models for three classes of compounds are developed by means of the quantum topological molecular similarity (QTMS) tool, which incorporates descriptors originating from the "Atoms in Molecules" (AIM) theory. Correlations obtained outperform the Hammett and other traditional parameters. The advantage of QTMS over semiempirical and empirical descriptors is demonstrated by the following r(2)/q(2) values: 0.920/0.891 (acids), 0.974/0.953 (anilines), and 0.952/0.884 (phenols).

Journal Article↗

PubMed2004

Quantitative structure-activity relationships of mutagenic activity from quantum topological descriptors: triazenes and halogenated hydroxyfuranones (mutagen-X) derivatives.

The mutagenic activity of 23 triazenes and, in a different set, of 24 halogenated hydroxyfuranones (MX derivatives) is quantitatively related to new features of contemporary molecular wave functions. Nowadays affordable computers are powerful enough to rapidly generate geometry-optimised ab initio wave functions at HF/3-21G*, HF/6-31G* and B3LYP/6-311 + G(2d,p) level for all molecules. The bonds of a common molecular skeleton are described by their ab initio bond lengths and local properties provided by the theory of quantum chemical topology (QCT). The chemometric analysis involves two types: one to generate a statistically validated quantitative model, and one to isolate the active center. In the former a genetic algorithm (GA) selects bond descriptors in order to optimise the cross-validation error, q2, followed by a full partial least squares (PLS) analysis, which also yields randomisation statistics. In the latter type principal components (PCs) are constructed from the original bond descriptors and their variables important to the projection (VIPs) are plotted in a histogram. This analysis suggests a preferred mechanistic pathway for the initial hydroxylation of the triazenes, an issue that has remained ambiguous so far. In the case of the hydroxyfuranones the proposed method aids the elucidation of a mechanistic ambivalence.

Algorithms↗

PubMed2004

Quantitative structure-activity relationships from optimised ab initio bond lengths: steroid binding affinity and antibacterial activity of nitrofuran derivatives.

The present day abundance of cheap computing power enables the use of quantum chemical ab initio data in Quantitative Structure-Activity Relationships (QSARs). Optimised bond lengths are a new such class of descriptors, which we have successfully used previously in representing electronic effects in medicinal and ecological QSARs (enzyme inhibitory activity, hydrolysis rate constants and pKas). Here we use AM1 and HF/3-21G* bond lengths in conjunction with Partial Least Squares (PLS) and a Genetic Algorithm (GA) to predict the Corticosteroid-Binding Globulin (CBG) binding activity of the classic steroid data set, and the antibacterial activity of nitrofuran derivatives. The current procedure, which does not require molecular alignment, produces good r2 and q2 values. Moreover, it highlights regions in the common steroid skeleton deemed relevant to the active regions of the steroids and nitrofuran derivatives.

Adrenal Cortex Hormones↗

PubMed2003

Atomic properties of selected biomolecules: quantum topological atom types of carbon occurring in natural amino acids and derived molecules.

We seek to recover rigorous atom types from amino acid wave functions. The atom types emerge from a cluster analysis operating on a set of seven atomic properties, including kinetic energy, volume, population, and dipole, quadrupole, octupole, and hexadecapole moments. These properties are acquired by partitioning the molecular electron density into quantum topological atoms. Wave functions are generated at the B3LYP/6-311+G(2d,p)//HF/6-31G(d) level for a sensible conformation of each of the 20 naturally occurring amino acids and smaller derived molecules, which together constitute a data set of 57 molecules. From this set 213 unique quantum topological carbons are obtained, which are linked according to the similarity of their properties. After introducing a statistical separation criterion, our cluster analysis proposes two representations: a cruder one with 5 atom types and a finer one with 21 atom types. The immediate coordination of the central carbon plays a major role in labeling the atom types.

Amino Acids↗