Pierre-Alain Carrupt

Bio: Pierre-Alain Carrupt is an academic researcher from University of Lausanne. The author has contributed to research in topics: Lipophilicity & Partition coefficient. The author has an hindex of 66, co-authored 422 publications receiving 15068 citations. Previous affiliations of Pierre-Alain Carrupt include University of Parma & University of London.

Molecular fields in quantitative structure–permeation relationships: the VolSurf approach

Abstract: Calculated molecular properties from 3D molecular fields of interaction energies have become a valuable approach to correlate 3D molecular structures with physicochemical and pharmacodynamic properties. In contrast, their use in correlations with pharmacokinetic properties is still poorly explored and exploited. 3D molecular fields can be obtained from ab initio, semiempirical or molecular mechanics levels of calculation. The newly developed procedure called VolSurf is able to compress the relevant information present in 3D maps into a few descriptors characterised by the simplicity of their use and interpretation. These descriptors can be quantitatively compared and used to build multivariate models correlating 3D molecular structures with biological responses. The VolSurf procedure is applied here to generate descriptors and models of structure–permeation relationships. The VolSurf procedure, which was originally designed to handle a medium amount of data, can easily be applied to problems of large size such as bioisostere databases, CombyChem databases and related approaches.

Predicting Blood−Brain Barrier Permeation from Three-Dimensional Molecular Structure

Abstract: Predicting blood-brain barrier (BBB) permeation remains a challenge in drug design. Since it is impossible to determine experimentally the BBB partitioning of large numbers of preclinical candidates, alternative evaluation methods based on computerized models are desirable. The present study was conducted to demonstrate the value of descriptors derived from 3D molecular fields in estimating the BBB permeation of a large set of compounds and to produce a simple mathematical model suitable for external prediction. The method used (VolSurf) transforms 3D fields into descriptors and correlates them to the experimental permeation by a discriminant partial least squares procedure. The model obtained here correctly predicts more than 90% of the BBB permeation data. By quantifying the favorable and unfavorable contributions of physicochemical and structural properties, it also offers valuable insights for drug design, pharmacological profiling, and screening. The computational procedure is fully automated and quite fast. The method thus appears as a valuable new tool in virtual screening where selection or prioritization of candidates is required from large collections of compounds.

Drug-protein binding: a critical review of analytical tools.

Abstract: The extent of drug binding to plasma proteins, determined by measuring the free active fraction, has a significant effect on the pharmacokinetics and pharmacodynamics of a drug. It is therefore highly important to estimate drug-binding ability to these macromolecules in the early stages of drug discovery and in clinical practice. Traditionally, equilibrium dialysis is used, and is presented as the reference method, but it suffers from many drawbacks. In an attempt to circumvent these, a vast array of different methods has been developed. This review focuses on the most important approaches used to characterize drug-protein binding. A description of the principle of each method with its inherent strengths and weaknesses is outlined. The binding affinity ranges, information accessibility, material consumption, and throughput are compared for each method. Finally, a discussion is included to help users choose the most suitable approach from among the wealth of methods presented.

Coumarins derivatives as dual inhibitors of acetylcholinesterase and monoamine oxidase

Abstract: A set of 17 coumarin and 2 chromone derivatives with known inhibitory activity toward monoamine oxidase (MAO) A and B were tested as acetylcholinesterase (AChE) inhibitors. All compounds inhibited AChE with values in the micromolar range (3−100 μM). A kinetic study showed that most compounds acted as noncompetitive AChE inhibitors. This finding may be of interest in the context of Alzheimer's disease because recent observations suggest that MAO and AChE inhibition might decrease β-amyloid deposition.

Molecular Lipophilicity Potential, a tool in 3D QSAR: Method and applications

Abstract: A new method is presented to calculate the Molecular Lipophilicity Potential (MLP). The method is validated by showing that the MLP thus generated on the solvent-accessible surface can be used to back-calculate log P. Because the MLP is shown to be sensitive to conformational effects, the MLP/log P relation is best sought by taking all conformers into account. The MLP method presented here can be used as a third field in CoMFA studies, as illustrated with two series of alpha 1-adrenoceptor ligands. In the first series, the steric, electrostatic and lipophilic fields are highly intercorrelated, and taken separately yield comparable models. In the second series of ligands, the best model is obtained with the lipophilic field alone, allowing insights into ligand-receptor interactions.

Membrane transporters in drug development.

Abstract: Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.

PaDEL‐descriptor: An open source software to calculate molecular descriptors and fingerprints

Abstract: Introduction PaDEL-Descriptor is a software for calculating molecular descriptors and fingerprints. The software currently calculates 797 descriptors (663 1D, 2D descriptors, and 134 3D descriptors) and 10 types of fingerprints. These descriptors and fingerprints are calculated mainly using The Chemistry Development Kit. Some additional descriptors and fingerprints were added, which include atom type electrotopological state descriptors, McGowan volume, molecular linear free energy relation descriptors, ring counts, count of chemical substructures identified by Laggner, and binary fingerprints and count of chemical substructures identified by Klekota and Roth. Methods PaDEL-Descriptor was developed using the Java language and consists of a library component and an interface component. The library component allows it to be easily integrated into quantitative structure activity relationship software to provide the descriptor calculation feature while the interface component allows it to be used as a standalone software. The software uses a Master/Worker pattern to take advantage of the multiple CPU cores that are present in most modern computers to speed up calculations of molecular descriptors. Results The software has several advantages over existing standalone molecular descriptor calculation software. It is free and open source, has both graphical user interface and command line interfaces, can work on all major platforms (Windows, Linux, MacOS), supports more than 90 different molecular file formats, and is multithreaded. Conclusion PaDEL-Descriptor is a useful addition to the currently available molecular descriptor calculation software. The software can be downloaded at http://padel.nus.edu.sg/software/padeldescriptor. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011