Pierre-Alain Carrupt

Pattern recognition study of QSAR substituent descriptors

SummaryParameter values for 59 common substituents and 74 descriptors used in QSAR studies were compiled. This data matrix was analysed by a variety of multivariate techniques. Linear regression confirmed that lipophilicity can be factorized into two terms, one related to molecular bulk and the other to polarity. Principal component analysis (PCA) of parameters revealed 5 significant principal components and a grouping of lipophilic, steric and electronic parameters. The different loadings of parameters with 5 PCA were also explored. The classification of substituents by cluster analysis (CA) proved rather disappointing. In contrast, the SIMCA method classified substituents of increasing bulk into 5 groups of increasing polarity.

Similarities of pharmacophoric patterns revealed by the MEP of metoclopramide, molindone and piquindone, a subgroup of dopamine D-2 receptor antagonists

Abstract Molecular electrostatic potential (MEP) calculations based on ab initio wave functions have been used to compare three compounds belonging to two distinct chemical series (substituted benzamides (metoclopramide) and indolones (piquindone and molindone)). These compounds have highly similar pharmacological properties at the receptor level (antagonists binding selectively to the dopamine D2 receptor and in a sodium-dependent manner). The MEPs of these compounds show close similarities and form a common pharmacophoric pattern.

Conformation, electrostatic potential and pharmacophoric pattern of orthopramides and other dopamine receptor antagonists

Abstract Theoretical and experimental conformational studies of orthopramides are reviewed and lead to the following conclusions for the compounds in solution. (i) For aminoethyl derivatives (e.g., metoclopramide) in the protonated form, folded and extended conformers of equal energy exist; the conformation of the non-protonated molecules is solvent-dependent. (ii) For 4-piperidyl derivatives (e.g., clebopride), only extended forms are possible under normal conditions. (iii) For 2-pyrrolidyl (e.g., sulpiride) and 3-pyrrolidyl derivatives (e.g., YM-08050), a relatively small energy difference exists between folded and extended forms. The extended form is thus postulated to be the one recognized by the receptor. Molecular electrostatic potential (MEP) calculations of the aromatic region of metoclopramide and halperidol show, in both cases, a positive and a negative edge. Superimposing the simplified and partial MEP of dopamine, metoclopramide and haloperidol leads to a pharmacophoric model of dopamine D-2 receptor ligands. These results are not compatible with a rigid and geometrical view of dopamine receptor topography.

Experimental and Theoretical-Studies on the Homoconjugation in Bicyclic Carbenium and Oxonium Ions in the Gas-Phase

Abstract Gas phase basicities and ab initio MO calculations show that non-vertical stabilization by the double bond in substituted 7-norborn-2-enyl and 7-noborna-2-dienyl cations remarkably decreases compared to the unsubstituted compounds.

Solvent-dependent lipophilicity and hydrogen-bonding capacity of 2-pyridylalkanols

Abstract The lipophilicity of homologous 2-pyridylkanols (2-pyridylmethanol to 5-(2-pyridyl)pentanol) was shown to be strongly solvent-dependent but neither log P values nor partial molar volumes are highly informative in terms of solute-solvent interactions. In contrast, Δ log P values quantittively express the capacity of the solutes to donate and accept H-bonds to and from the solvent. These capacities are molecular rather than fragmental properties in that they depend not only on the functional groups, but also on their intramolecular relationships.

The influence of aromatic substituents on the binding of substituted benzamides to dopamine D-2 receptors: congruent QSAR and MEP analyses

tes of MTX and anti-tumour monoclonal antibodies

The influence of hydration and structure-promoting effects on the viscosity of binary solvent mixtures

ddwin et a1 1986). Overall, these and other related studies (Corvalan et d 1987) indicate that modification of drug biodistribudon with monoclonal antibodies and/or tissue specific targeting with complexes formed with hybrid antibodies may be valid approaches to prolongation of drug survival and/or site-specific targeting. The degree of drug loading of monoclonal antibodies, with theoretical of two molecules per molecule with anti-drug antibody and one molecule per molecule of hybrid antibody, might be a limitation, since the amount of antibody required to carry conventional therapeutic doses of drug would be very high. In addition the extent ofextravasation of antibody is much smaller than that of drugs. But, as this study shows, the survival of drug is markedly prolonged simply with the anti-drug antibody, and the additional site targeting effect possible with hybrid antibodies might mean the possible use of greatly reduced doses of drug.

Dynamic representation of quantum chemical results using computer graphics: Molecular rearrangements, art or science?

Abstract The viscosity of binary mixtures of water and aprotic or protic polar solvents has been examined and compared with the viscosity of binary mixtures of aprotic polar solvents. In the latter case, ideal behaviour is seen in the sense that the viscosity of the mixture can be expressed as a sum of viscosities. On the contrary, mixtures of water plus a polar solvent (either protic or aprotic) show a maximum in viscosity (expressed as Δη max ) corresponding to a well-defined molar ratio of components (expressed as a hydration number, HN max ) and resulting from specific water-solvent interactions. Relationships between the two viscosity parameters and various physicochemical properties of the solvents have been investigated, showing that HN max increases or decreases with the capacity of solvents to donate or accept H-bonds, respectively. In contrast, Δη max results from structure-promoting effects associated with the capacity of the solvent to accept H-bonds from water and to interact hydrophobically

Dynamic modeling of chemical reactions: the Diels-Alder cycloaddition

Abstract An interactive computer graphics equipment is used as an output device for representing the results of quantum chemical calculations. The advantages of such displays are illustrated by the description of several applications: (i) interactive visualization of molecular properties and (ii) dynamic representation of unimolecular rearrangements. Several examples are chosen among the latter group of applications: reversible formation of cyclobutene from 1,3-butadiene, intramolecular migration of a methyl group over an allyl substrate, and pseudo-rotation of a seven-membered heterocyclic compound. It is shown that the 3D representation of reaction paths is generally an involved task since, as the geometrical data base is most often incomplete, it is necessary to find a middle ground between chemically reasonable and aesthetically pleasant pictures, thus leading to a technique which lies somewhere in between art and science.

The MPTP story: MAO activates tetrahydropyridine derivatives to toxins causing parkinsonism.

Abstract In order to visualize the stereochemical aspects of the Diels-Alder model cycloaddition of ethylene on butadiene, we developed a computer graphics animated model. The structural data base was deduced from MINDO/3 calculations, and the application program makes it possible to display in detail the different steps of the reaction mechanism. The scope of the application has been enlarged by a similar representation of the Diels-Alder cycloaddition of bis (methylene)—2,3 bicyclo [2.2.1]heptane to ethylene. Both of these examples suggest that molecular graphics is an ideal tool for visualizing and understanding the stereochemistry of complex chemical reactions.