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Per Artursson - One of the best experts on this subject based on the ideXlab platform.
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absorption classification of oral drugs based on Molecular Surface properties
Journal of Medicinal Chemistry, 2003Co-Authors: Christel A. S. Bergström, Kristina Luthman, Melissa Strafford, Lucia Lazorova, Alex Avdeef, Per ArturssonAbstract:The aim of this study was to investigate whether easily calculated and comprehended Molecular Surface properties can predict drug solubility and permeability with sufficient accuracy to allow theoretical absorption classification of drug molecules. For this purpose, structurally diverse, orally administered model drugs were selected from the World Health Organization (WHO)'s list of essential drugs. The solubility and permeability of the drugs were determined using well-established in vitro methods in highly accurate experimental settings. Descriptors for Molecular Surface area were generated from low-energy conformations obtained by conformational analysis using Molecular mechanics calculations. Correlations between the calculated Molecular Surface area descriptors, on one hand, and solubility and permeability, on the other, were established with multivariate data analysis (partial least squares projection to latent structures (PLS)) using training and test sets. The obtained models were challenged with ...
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experimental and computational screening models for prediction of aqueous drug solubility
Pharmaceutical Research, 2002Co-Authors: Christel A. S. Bergström, Kristina Luthman, Ulf Norinder, Per ArturssonAbstract:Purpose. To devise experimental and computational models to predict aqueous drug solubility. Methods. A simple and reliable modification of the shake flask method to a small-scale format was devised, and the intrinsic solubilities of 17 structurally diverse drugs were determined. The experimental solubility data were used to investigate the accuracy of commonly used theoretical and semiexperimental models for prediction of aqueous drug solubility. Computational models for prediction of intrinsic solubility, based on lipophilicity and Molecular Surface areas, were developed. Results. The intrinsic solubilities ranged from 0.7 ng/mL to 6.0 mg/mL, covering a range of almost seven log10 units, and the values determined with the new small-scale shake flask method agreed well with published solubility data. Solubility data computed with established theoretical models agreed poorly with the experimentally determined solubilities, but the correlations improved when experimentally determined melting points were included in the models. A new, fast computational model based on lipophilicity and partitioned Molecular Surface areas, which predicted intrinsic drug solubility with a good accuracy (R 2of 0.91 and RMSEtr of 0.61) was devised. Conclusions. A small-scale shake flask method for determination of intrinsic drug solubility was developed, and a promising alternative computational model for the theoretical prediction of aqueous drug solubility was proposed.
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prediction of membrane permeability to peptides from calculated dynamic Molecular Surface properties
Pharmaceutical Research, 1999Co-Authors: Patric Stenberg, Kristina Luthman, Per ArturssonAbstract:Purpose. To develop a theoretical method for prediction of transcellular permeability to peptides.
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evaluation of dynamic polar Molecular Surface area as predictor of drug absorption comparison with other computational and experimental predictors
Journal of Medicinal Chemistry, 1998Co-Authors: Katrin Palm, Gert Strandlund, Kristina Luthman, Anna-lena Ungell, Farideh Beigi, Per Lundahl, Per ArturssonAbstract:The relationship between various Molecular descriptors and transport of drugs across the intestinal epithelium was evaluated. The monolayer permeability (Pc) of human intestinal Caco-2 cells to a series of nine β-receptor-blocking agents was investigated in vitro. The dynamic polar Molecular Surface area (PSAd) of the compounds was calculated from all low-energy conformations identified in Molecular mechanics calculations in vacuum and in simulated chloroform and water environments. For most of the investigated drugs, the effects of the different environments on PSAd were small. The exception was H 216/44, which is a large flexible compound containing several functional groups capable of hydrogen bonding (PSAd,chloroform = 70.8 A2 and PSAd,water = 116.6 A2). The relationship between Pc and PSAd was stronger than those between Pc and the calculated octanol/water distribution coefficients (log Dcalc) or the experimentally determined immobilized liposome chromatography (ILC) retention. Pc values for two new ...
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polar Molecular Surface properties predict the intestinal absorption of drugs in humans
Pharmaceutical Research, 1997Co-Authors: Katrin Palm, Kristina Luthman, Patric Stenberg, Per ArturssonAbstract:Purpose. A theoretical method has been devised for prediction of drug absorption after oral administration to humans. Methods. Twenty structurally diverse model drugs, ranging from 0.3 to 100% absorbed, were investigated. The compounds also displayed diversity in physicochemical properties such as lipophilicity, hydrogen bonding potential and Molecular size. The dynamic Molecular Surface properties of the compounds were calculated, taking into account their three-dimensional shape and flexibility. Results. An excellent sigmoidal relationship was established between the absorbed fraction after oral administration to humans (FA) and the dynamic polar Molecular Surface area (PSAd) (r2 = 0.94). The relationship was stronger than those obtained for more established predictors of drug absorption. Drugs that are completely absorbed (FA > 90%) had a PSAd ≤ 60 A2 while drugs that are 140 A2. Conclusions. The results indicate that PS Ad can be used to differentiate poorly absorbed drugs at an early stage of the drug discovery process.
Kristina Luthman - One of the best experts on this subject based on the ideXlab platform.
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absorption classification of oral drugs based on Molecular Surface properties
Journal of Medicinal Chemistry, 2003Co-Authors: Christel A. S. Bergström, Kristina Luthman, Melissa Strafford, Lucia Lazorova, Alex Avdeef, Per ArturssonAbstract:The aim of this study was to investigate whether easily calculated and comprehended Molecular Surface properties can predict drug solubility and permeability with sufficient accuracy to allow theoretical absorption classification of drug molecules. For this purpose, structurally diverse, orally administered model drugs were selected from the World Health Organization (WHO)'s list of essential drugs. The solubility and permeability of the drugs were determined using well-established in vitro methods in highly accurate experimental settings. Descriptors for Molecular Surface area were generated from low-energy conformations obtained by conformational analysis using Molecular mechanics calculations. Correlations between the calculated Molecular Surface area descriptors, on one hand, and solubility and permeability, on the other, were established with multivariate data analysis (partial least squares projection to latent structures (PLS)) using training and test sets. The obtained models were challenged with ...
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experimental and computational screening models for prediction of aqueous drug solubility
Pharmaceutical Research, 2002Co-Authors: Christel A. S. Bergström, Kristina Luthman, Ulf Norinder, Per ArturssonAbstract:Purpose. To devise experimental and computational models to predict aqueous drug solubility. Methods. A simple and reliable modification of the shake flask method to a small-scale format was devised, and the intrinsic solubilities of 17 structurally diverse drugs were determined. The experimental solubility data were used to investigate the accuracy of commonly used theoretical and semiexperimental models for prediction of aqueous drug solubility. Computational models for prediction of intrinsic solubility, based on lipophilicity and Molecular Surface areas, were developed. Results. The intrinsic solubilities ranged from 0.7 ng/mL to 6.0 mg/mL, covering a range of almost seven log10 units, and the values determined with the new small-scale shake flask method agreed well with published solubility data. Solubility data computed with established theoretical models agreed poorly with the experimentally determined solubilities, but the correlations improved when experimentally determined melting points were included in the models. A new, fast computational model based on lipophilicity and partitioned Molecular Surface areas, which predicted intrinsic drug solubility with a good accuracy (R 2of 0.91 and RMSEtr of 0.61) was devised. Conclusions. A small-scale shake flask method for determination of intrinsic drug solubility was developed, and a promising alternative computational model for the theoretical prediction of aqueous drug solubility was proposed.
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prediction of membrane permeability to peptides from calculated dynamic Molecular Surface properties
Pharmaceutical Research, 1999Co-Authors: Patric Stenberg, Kristina Luthman, Per ArturssonAbstract:Purpose. To develop a theoretical method for prediction of transcellular permeability to peptides.
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evaluation of dynamic polar Molecular Surface area as predictor of drug absorption comparison with other computational and experimental predictors
Journal of Medicinal Chemistry, 1998Co-Authors: Katrin Palm, Gert Strandlund, Kristina Luthman, Anna-lena Ungell, Farideh Beigi, Per Lundahl, Per ArturssonAbstract:The relationship between various Molecular descriptors and transport of drugs across the intestinal epithelium was evaluated. The monolayer permeability (Pc) of human intestinal Caco-2 cells to a series of nine β-receptor-blocking agents was investigated in vitro. The dynamic polar Molecular Surface area (PSAd) of the compounds was calculated from all low-energy conformations identified in Molecular mechanics calculations in vacuum and in simulated chloroform and water environments. For most of the investigated drugs, the effects of the different environments on PSAd were small. The exception was H 216/44, which is a large flexible compound containing several functional groups capable of hydrogen bonding (PSAd,chloroform = 70.8 A2 and PSAd,water = 116.6 A2). The relationship between Pc and PSAd was stronger than those between Pc and the calculated octanol/water distribution coefficients (log Dcalc) or the experimentally determined immobilized liposome chromatography (ILC) retention. Pc values for two new ...
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polar Molecular Surface properties predict the intestinal absorption of drugs in humans
Pharmaceutical Research, 1997Co-Authors: Katrin Palm, Kristina Luthman, Patric Stenberg, Per ArturssonAbstract:Purpose. A theoretical method has been devised for prediction of drug absorption after oral administration to humans. Methods. Twenty structurally diverse model drugs, ranging from 0.3 to 100% absorbed, were investigated. The compounds also displayed diversity in physicochemical properties such as lipophilicity, hydrogen bonding potential and Molecular size. The dynamic Molecular Surface properties of the compounds were calculated, taking into account their three-dimensional shape and flexibility. Results. An excellent sigmoidal relationship was established between the absorbed fraction after oral administration to humans (FA) and the dynamic polar Molecular Surface area (PSAd) (r2 = 0.94). The relationship was stronger than those obtained for more established predictors of drug absorption. Drugs that are completely absorbed (FA > 90%) had a PSAd ≤ 60 A2 while drugs that are 140 A2. Conclusions. The results indicate that PS Ad can be used to differentiate poorly absorbed drugs at an early stage of the drug discovery process.
Yuri V Sergeev - One of the best experts on this subject based on the ideXlab platform.
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novel computer program for fast exact calculation of accessible and Molecular Surface areas and average Surface curvature
Journal of Computational Chemistry, 2002Co-Authors: Oleg V Tsodikov, Thomas M Record, Yuri V SergeevAbstract:New computer programs, SurfRace and FastSurf, perform fast calculations of the solvent accessible and Molecular (solvent excluded) Surface areas of macromolecules. Program SurfRace also calculates the areas of cavities inaccessible from the outside. We introduce the definition of average curvature of Molecular Surface and calculate average Molecular Surface curvatures for each atom in a structure. All Surface area and curvature calculations are analytic and therefore yield exact values of these quantities. High calculation speed of this software is achieved primarily by avoiding computationally expensive mathematical procedures wherever possible and by efficient handling of Surface data structures. The programs are written initially in the language C for PCs running Windows 2000/98/NT, but their code is portable to other platforms with only minor changes in input-output procedures. The algorithm is robust and does not ignore either multiplicity or degeneracy of atomic overlaps. Fast, memory-efficient and robust execution make this software attractive for applications both in computationally expensive energy minimization algorithms, such as docking or Molecular dynamics simulations, and in stand-alone Surface area and curvature calculations. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 600–609, 2002
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novel computer program for fast exact calculation of accessible and Molecular Surface areas and average Surface curvature
Journal of Computational Chemistry, 2002Co-Authors: Oleg V Tsodikov, Thomas M Record, Yuri V SergeevAbstract:New computer programs, SurfRace and FastSurf, perform fast calculations of the solvent accessible and Molecular (solvent excluded) Surface areas of macromolecules. Program SurfRace also calculates the areas of cavities inaccessible from the outside. We introduce the definition of average curvature of Molecular Surface and calculate average Molecular Surface curvatures for each atom in a structure. All Surface area and curvature calculations are analytic and therefore yield exact values of these quantities. High calculation speed of this software is achieved primarily by avoiding computationally expensive mathematical procedures wherever possible and by efficient handling of Surface data structures. The programs are written initially in the language C for PCs running Windows 2000/98/NT, but their code is portable to other platforms with only minor changes in input-output procedures. The algorithm is robust and does not ignore either multiplicity or degeneracy of atomic overlaps. Fast, memory-efficient and robust execution make this software attractive for applications both in computationally expensive energy minimization algorithms, such as docking or Molecular dynamics simulations, and in stand-alone Surface area and curvature calculations.
Jane S. Murray - One of the best experts on this subject based on the ideXlab platform.
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quantitative analyses of Molecular Surface electrostatic potentials in relation to hydrogen bonding and co crystallization
Crystal Growth & Design, 2015Co-Authors: Peter Politzer, Jane S. MurrayAbstract:The important role that electrostatic potentials computed on Molecular Surfaces can have in designing new materials via co-crystallization is discussed and illustrated. The locally most positive and most negative values of the Surface electrostatic potential identify and rank sites for hydrogen bonding (complementing Etter’s rules), halogen bonding, and other types of noncovalent interactions. It is shown that the primary interactions are often better viewed as involving small regions rather than specific atoms. Recent applications of cocrystallization as a means of reducing the hazard associated with energetic materials are briefly examined.
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Molecular Surface electrostatic potentials and anesthetic activity
Journal of Molecular Modeling, 2007Co-Authors: Gavin Trogdon, Jane S. Murray, Monica C Concha, Peter PolitzerAbstract:General anesthetics apparently act through weak, noncovalent and reversible interactions with certain sites in appropriate brain proteins. As a means of gaining insight into the factors underlying anesthetic potency, we have analyzed the computed electrostatic potentials V S(r) on the Surfaces of 20 molecules with activities that vary between zero and high. Our results are fully consistent with, and help to interpret, what has been observed experimentally. We find that an intermediate level of internal charge separation is required; this is measured by Π, the average absolute deviation of V S(r), and the approximate window is 7 < Π < 13 kcal mol−1. This fits in well with the fact that anesthetics need to be lipid soluble, but also to have some degree of hydrophilicity. We further show that polyhalogenated alkanes and ethers, which include the most powerful known anesthetics, have strong positive potentials, V S,max, associated with their hydrogens, chlorines and bromines (but not fluorines). These positive sites may impede the functioning of key brain proteins, for example by disrupting their normal hydrogen-bond patterns. It has indeed been recognized for some time that the most active polyhalogenated alkanes and ethers contain hydrogens usually in combination with chlorines and/or bromines.
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the complementary roles of Molecular Surface electrostatic potentials and average local ionization energies with respect to electrophilic processes
International Journal of Quantum Chemistry, 2002Co-Authors: Peter Politzer, Jane S. Murray, Monica C ConchaAbstract:We focus upon two properties, the electrostatic potential V(r) and the average local ionization energy . When evaluated on Molecular Surfaces, VS(r) and can be useful tools for analyzing and predicting reactive behavior. VS(r) is most reliable with respect to noncovalent interactions; when electrophilic attack and some degree of charge transfer are involved, then the combination of VS(r) and can be quite effective. They play complementary roles: VS(r) reveals the regions of the molecule to which an electrophile would initially be attracted, and indicates the ease of charge transfer at these and other sites. Four examples of such complementarity are discussed, involving benzene derivatives, guanine and cytosine, furan and pyrrole, and binary hydrides. © 2002 John Wiley & Sons, Inc. Int J Quantum Chem, 2002
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statistical analysis of the Molecular Surface electrostatic potential an approach to describing noncovalent interactions in condensed phases
Journal of Molecular Structure-theochem, 1998Co-Authors: Jane S. Murray, Peter PolitzerAbstract:Abstract We discuss various means of characterizing the pattern of the electrostatic potential on a Molecular Surface. These include determination of the most positive and most negative values of the potential, its average deviation, and its variance. The latter, in conjunction with a measure of the degree of balance between the contributions from the positive and negative regions, has proven to be particularly useful in developing analytical representations of condensed phase properties that depend upon noncovalent interactions. Some applications are briefly reviewed.
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Relationships of Molecular Surface electrostatic potentials to some macroscopic properties
1996Co-Authors: Jane S. Murray, Tore Brinck, Peter PolitzerAbstract:Abstract An approach to quantifying key features of the electrostatic potential on the Surface of a molecule is reviewed. Analytical relationships for heat of fusion, Surface tension, and liquid and crystal densities are presented and discussed.
Katrin Palm - One of the best experts on this subject based on the ideXlab platform.
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evaluation of dynamic polar Molecular Surface area as predictor of drug absorption comparison with other computational and experimental predictors
Journal of Medicinal Chemistry, 1998Co-Authors: Katrin Palm, Gert Strandlund, Kristina Luthman, Anna-lena Ungell, Farideh Beigi, Per Lundahl, Per ArturssonAbstract:The relationship between various Molecular descriptors and transport of drugs across the intestinal epithelium was evaluated. The monolayer permeability (Pc) of human intestinal Caco-2 cells to a series of nine β-receptor-blocking agents was investigated in vitro. The dynamic polar Molecular Surface area (PSAd) of the compounds was calculated from all low-energy conformations identified in Molecular mechanics calculations in vacuum and in simulated chloroform and water environments. For most of the investigated drugs, the effects of the different environments on PSAd were small. The exception was H 216/44, which is a large flexible compound containing several functional groups capable of hydrogen bonding (PSAd,chloroform = 70.8 A2 and PSAd,water = 116.6 A2). The relationship between Pc and PSAd was stronger than those between Pc and the calculated octanol/water distribution coefficients (log Dcalc) or the experimentally determined immobilized liposome chromatography (ILC) retention. Pc values for two new ...
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polar Molecular Surface properties predict the intestinal absorption of drugs in humans
Pharmaceutical Research, 1997Co-Authors: Katrin Palm, Kristina Luthman, Patric Stenberg, Per ArturssonAbstract:Purpose. A theoretical method has been devised for prediction of drug absorption after oral administration to humans. Methods. Twenty structurally diverse model drugs, ranging from 0.3 to 100% absorbed, were investigated. The compounds also displayed diversity in physicochemical properties such as lipophilicity, hydrogen bonding potential and Molecular size. The dynamic Molecular Surface properties of the compounds were calculated, taking into account their three-dimensional shape and flexibility. Results. An excellent sigmoidal relationship was established between the absorbed fraction after oral administration to humans (FA) and the dynamic polar Molecular Surface area (PSAd) (r2 = 0.94). The relationship was stronger than those obtained for more established predictors of drug absorption. Drugs that are completely absorbed (FA > 90%) had a PSAd ≤ 60 A2 while drugs that are 140 A2. Conclusions. The results indicate that PS Ad can be used to differentiate poorly absorbed drugs at an early stage of the drug discovery process.
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correlation of drug absorption with Molecular Surface properties
Journal of Pharmaceutical Sciences, 1996Co-Authors: Katrin Palm, Gert Strandlund, Kristina Luthman, Anna-lena Ungell, Per ArturssonAbstract:The correlation between dynamic Surface properties of drug molecules and drug absorption in two common in vitro models of the intestinal wall (Caco-2 monolayers and rat intestinal segments) has been investigated. A homologous series of β-adrenoreceptor antagonists were used as model compounds. Dynamic Molecular Surface properties, considering all low-energy conformations, of the compounds were calculated. The flexibility of the molecules was studied by Molecular mechanics calculations (MM2) and the van der Waals' (vdW), and water accessible Surface areas were calculated and averaged according to a Boltzmann distribution. Excellent correlations were obtained between the dynamic polar vdW Surface areas and cell permeabilities in Caco-2 cells and rat ileum (r2 = 0.99 and 0.92, respectively). These correlations were stronger than those between calculated octanol/buffer partition coefficients (log Doct,7.4) and permeability (r2 = 0.80 and 0.73, respectively). Moreover, the calculated log Doct,7.4 values failed to rank the permeability coefficients through Caco-2 monolayers and rat ileum in the correct order. The results indicate that dynamic polar Surface area is a promising alternative model for the prediction of oral drug absorption.