Adam Ibrahim - Profile on Academia.edu (original) (raw)
Papers by Adam Ibrahim
International journal of pharmaceutics, 2007
Data on distribution coefficients from blood or plasma to rat skin and rabbit skin have been comp... more Data on distribution coefficients from blood or plasma to rat skin and rabbit skin have been compiled. From previous work on blood/plasma to brain or to muscle it is apparent that distributions from blood and plasma can be combined, and we show that it is possible to combine data on distribution to rat skin and rabbit skin. The combined set of blood/plasma distribution to rat and rabbit skin for 59 compounds, as logPskin, can be correlated through a linear free energy equation with a correlation coefficient of 0.856 and a standard deviation of 0.26 log units. The predictive capability of the equation has been assessed through training and test sets, and it is shown that the S.D. value of 0.26 log units is a good estimate of the predictive ability. The equation for logPskin has been compared to equations for a large number of possible model processes, using two mathematical methods. It is shown that there is no process amongst those we have examined that has any advantage over the pr...
Pest Management Science, 2013
The prediction of blood-tissue partitions, water-skin partitions and skin permeation for agrochem... more The prediction of blood-tissue partitions, water-skin partitions and skin permeation for agrochemicals.
Determination of sets of solute descriptors from chromatographic measurements
Journal of Chromatography A, 2004
The use of gas-liquid chromatographic (GLC) retention data to obtain sets of solute descriptors i... more The use of gas-liquid chromatographic (GLC) retention data to obtain sets of solute descriptors is outlined, with reference to the schemes of Laffort and of Weckwerth. The method of Snyder and Dolan to obtain a set of solute descriptors from reverse phase high performance chromatographic (RP-HPLC) measurements is described. The work of Abraham on the construction of solvation parameters, or descriptors, from water-solvent partitions, GLC retention data and RP-HPLC data is considered in some detail. A comparison is made between the schemes of Laffort, Weckwerth and Abraham, and it is shown that the latter two yield exactly the same fits for a test data set of gas-methanol partition coefficients, although the distribution of chemical information amongst the terms in the multiple linear regressions is not quite the same. A comparison between the above 'experimental' descriptors and theoretical descriptors is made, and it is shown that the experimental Abraham and the theoretical Klamt descriptors encode almost the same chemical information. It is concluded that for processes that entail transfer of a solute from one phase to another, only a small number of solute descriptors, no more than five or six, is needed to provide a reasonably accurate analysis of the process.
Distribution coefficients, Kbi00d and KtiSSues (or biophase), from the gas phase to blood and gas... more Distribution coefficients, Kbi00d and KtiSSues (or biophase), from the gas phase to blood and gas phase to tissues (plasma, brain, fat, heart, liver, lung, kidney, muscle, urine, saline and olive oil) have been collected for large number of volatile organic compounds (VOCs). For these datasets of VOCs, linear free energy relationships (LFERs) have been established and Abraham equations have successfully been constructed to predict these distributions. It has also been shown that human and rat data for the air to blood and air to tissue distribution of VOCs can be combined. The differences in the two data sets, for the common compounds are smaller than the estimated inter-laboratory experimental error. The combination of the log KtiSSue values with values for air to blood yields distribution coefficients from blood to tissue, as log PtiSSue-Equations have successfully been constructed to predict these distributions. From a large amount of collected data on the distribution of drugs f...
Drug Discovery Today, 2002
and H-bond acidity and H-bond basicity. These descriptors can be rapidly estimated from structure... more and H-bond acidity and H-bond basicity. These descriptors can be rapidly estimated from structure by a fragment scheme and used to predict physicochemical and transport properties of drug candidates (e.g. logP, solubility, gastrointestinal absorption, permeability and blood-brain distribution). The solvation equations can be interpreted to provide a qualitative chemical insight into biological partition and transport mechanisms. Applications to blood-brain partition and human intestinal absorption (HIA) are discussed.
Air to Muscle and Blood/Plasma to Muscle Distribution of Volatile Organic Compounds and Drugs: Linear Free Energy Analyses
Chemical Research in Toxicology, 2006
Distribution coefficients, K(mus), from the gas phase to the muscle have been collected for volat... more Distribution coefficients, K(mus), from the gas phase to the muscle have been collected for volatile organic compounds (VOCs). For 114 VOCs, a linear free energy relationship (LFER) yields an equation for log K(mus) with R(2) = 0.944 and SD = 0.267; construction of a training and test set shows that the LFER can predict further values to around 0.30 log units. The combination of the log K(mus) values with values for air to blood yields distribution coefficients from blood to muscle, log P(mus), for 110 VOCs; the corresponding LFER has R(2) = 0.537 and SD = 0.207 and a predictive capability of 0.22 log units. We also collected data on the distribution of drugs from blood or plasma to muscle and showed that the two sets of data can be combined. A LFER for blood/plasma to muscle for 59 drugs has R(2) = 0.745 and SD = 0.253 and a predictive capability of 0.25 log units. Finally, we show that the in vitro data on VOCs and the in vivo data on drugs can be combined; a LFER on the total data for 163 compounds has R(2) = 0.595, SD = 0.220, and a predictive capability of about 0.25 log units.
European Journal of Medicinal Chemistry, 2006
Partition coefficients, Kfat, from air to human fat and to rat fat have been collected for 129 vo... more Partition coefficients, Kfat, from air to human fat and to rat fat have been collected for 129 volatile organic compounds, VOCs. A linear free energy relationship, LFER, correlates the 129 values of logKfat with R2=0.958 and a standard deviation, S.D., of 0.194 log units. Use of training and test sets gives a predictive assessment of around 0.20 log units. Combination
Chemical Research in Toxicology, 2005
Partition coefficients, K blood , for volatile organic compounds from air to blood have been coll... more Partition coefficients, K blood , for volatile organic compounds from air to blood have been collected for 155 compounds (air to human blood) and 127 compounds (air to rat blood). For 86 common compounds, the average error, AE, between the two sets of log K blood values is 0.12 log units, somewhat smaller than our estimated interlaboratory average SD value of around 0.16 log units. We conclude that with regard to experimental errors, there is no significant difference between K blood values in human blood and in rat blood. There are 196 compounds for which either or both K blood (human) and K blood (rat) are available. A training set of 98 compounds could be fitted with the Abraham solvation parameters with R 2 ) 0.933 and SD ) 0.34 log units. The training equation was then used to predict the test set of values with AE ) 0.04 log units, SD ) 0.33 log units, and an average absolute error, AAE, of 0.25 log units. A second training and test set yielded similar values: AE ) 0.01, SD ) 0.39, and AAE ) 0.29 log units. It is concluded that it is possible to construct an equation capable of predicting further values of log K blood to around 0.30 log units. Because the descriptors used in the correlation equations can be predicted from structure, it is now possible to predict log K blood for any chemical structure.
Journal of Chemical Information and Modeling, 2006
Literature values of gas to olive oil partition coefficients at 37°C have been assembled for 218 ... more Literature values of gas to olive oil partition coefficients at 37°C have been assembled for 218 compounds. Application of an Abraham linear free energy equation correlates 215 compounds with R 2 ) 0.981 and a standard deviation, SD, of 0.196 log units. One hundred and eight compounds were then used as a training set, and the resulting equation was used to predict the remaining 107 compounds with an average error of 0.025, an absolute average error of 0.150, and a standard deviation of 0.224 log units. The linear free energy equation shows that as a solvent olive oil is not very polar but is reasonably basic, although with a weaker hydrogen bond base than ethyl acetate or acetone, and has no hydrogen bond acidity. The coefficients for partition from the gas phase to biological phases such as blood and brain lie between those for water and olive oil, which explains why gas to biological phase partition can be described in an empirical way by a combination of gas to olive oil and gas to saline coefficients
Partition of compounds from gas to water and from gas to physiological saline at 310 K: Linear free energy relationships
Fluid Phase Equilibria, 2007
Data have been assembled on gas to water partition coefficients for 374 compounds at 310K. It is ... more Data have been assembled on gas to water partition coefficients for 374 compounds at 310K. It is shown that an Abraham solvation equation with five descriptors can be used to correlate 350 such values, as logKW(310), with R2=0.994 and S.D.=0.154log units. Division into a training set and a test set shows that there is no bias in predictions and that
A simple method for estimating in vitro air-tissue and in vivo blood-tissue partition coefficients
Chemosphere, 2015
A simple method is reported for the estimation of in vivo air-tissue partition coefficients of VO... more A simple method is reported for the estimation of in vivo air-tissue partition coefficients of VOCs and of in vitro blood-tissue partition coefficients for volatile organic compounds and other compounds. Linear free energy relationships for tissues such as brain, muscle, liver, lung, kidney, heart, skin and fat are available and once the Abraham descriptors are known for a compound, no more than simple arithmetic is required to estimate air-tissue and blood-tissue partitions.
Journal of Pharmaceutical Sciences, 2006
Literature values of the in vivo distribution (BB) of drugs from blood, plasma, or serum to rat b... more Literature values of the in vivo distribution (BB) of drugs from blood, plasma, or serum to rat brain have been assembled for 207 compounds (233 data points). We find that data on in vivo distribution from blood, plasma, and serum to rat brain can all be combined. Application of our general linear free energy relationship (LFER) to the 207 compounds yields an equation in log BB, with R 2 ¼ 0.75 and a standard deviation, SD, of 0.33 log units. An equation for a training set predicts the test set of data with a standard deviation of 0.31 log units. We further find that the in vivo data cannot simply be combined with in vitro data on volatile organic and inorganic compounds, because there is a systematic difference between the two sets of data. Use of an indicator variable allows the two sets to be combined, leading to a LFER equation for 302 compounds (328 data points) with R 2 ¼ 0.75 and SD ¼ 0.30 log units. A training equation was then used to predict a test set with SD ¼ 0.25 log units. ß
Predicting Penetration Across the Blood-Brain Barrier from Simple Descriptors and Fragmentation Schemes
Journal of Chemical Information and Modeling, 2007
The ability to cross the blood brain barrier (BBB), sometimes expressed as BBB+ and BBB-, is a ve... more The ability to cross the blood brain barrier (BBB), sometimes expressed as BBB+ and BBB-, is a very important property in drug design. Several computational methods have been employed for the prediction of BBB-penetrating (BBB+) and nonpenetrating (BBB-) compounds with overall accuracies from 75 to 97%. However, most of these models use a large number of descriptors (67-199), and it is not easy to implement the models in order to predict values of BBB+/-. In this work, 19 simple molecular descriptors calculated from Algorithm Builder and fragmentation schemes were used for the analysis of 1593 BBB+/- data. The results show that hydrogen-bonding properties of compounds play a very important role in modeling BBB penetration. Several BBB models based on hydrogen-bonding properties, such as Abraham descriptors, polar surface area (PSA), and number of hydrogen bonding donors and acceptors, have been built using binomial-PLS analysis. The results show that the overall classification accuracy for a training set is over 90%, and overall prediction accuracy for a test set is over 95%.
European Journal of Medicinal Chemistry, 2008
Values of in vitro gas to lung partition coefficients, K lung , of VOCs have been collected from ... more Values of in vitro gas to lung partition coefficients, K lung , of VOCs have been collected from the literature. For 44 VOCs, application of the Abraham solvation equation to log K lung yielded a correlation with R 2 ¼ 0.968 and S.D. ¼ 0.25 log units. Combination of the log K lung values with log K blood values leads to in vitro blood to lung partition coefficients, log P lung for 43 VOCs; an Abraham solvation equation correlated these values with a very poor R 2 ¼ 0.262 but with a very good S.D. ¼ 0.190 log units.
European Journal of Medicinal Chemistry, 2006
Partition coefficients, K brain , for volatile organic compounds, VOCs, from air to brain have be... more Partition coefficients, K brain , for volatile organic compounds, VOCs, from air to brain have been collected for 81 compounds (air to human brain and air to rat brain). For the 81 VOCs a linear free energy equation (LFER) correlates log K brain with R 2 = 0.923 and S.D. = 0.346 log units. Use of training and test sets gives a predictive assessment of 0.35-0.40 log units. Combination of log K brain with our previously listed values of log K blood enables blood to brain partition, as log P b-brain , to be obtained for 78 VOCs. These values can be correlated with R 2 = 0.725 and S.D. = 0.203 log units; use of training and test sets allows a predictive assessment for log P b-brain of 0.16-0.20 log units. Values for air to plasma were available for 21 VOCs. When these data were combined with the data on air to blood and air to brain, values for partition between (blood or plasma) to brain, P bp-brain , were available for 99 VOCs. A LFER correlates this data with R 2 = 0.703 and S.D. = 0.197 log units; use of training and test sets allows a predictive assessment for log P bp-brain of 0.15-0.20 log units.
European Journal of Medicinal Chemistry, 2007
Values of in vitro air to liver partition coefficients, K liver , of VOCs have been collected fro... more Values of in vitro air to liver partition coefficients, K liver , of VOCs have been collected from the literature. For 124 VOCs, application of the Abraham solvation equation to log K liver yielded a correlation equation with R 2 ¼ 0.927 and SD ¼ 0.26 log units. Combination of the log K liver values with log K blood values leads to in vitro blood to liver partition coefficients, as log P liver for VOCs; an Abraham solvation equation can correlate 125 such values with R 2 ¼ 0.583 and SD ¼ 0.23 log units. Values of in vivo log P liver for 85 drugs were collected, and were correlated with R 2 ¼ 0.522 and SD ¼ 0.42 log units. When the log P liver values for VOCs and drugs were combined, an Abraham solvation equation could correlate the 210 compounds with R 2 ¼ 0.544 and SD ¼ 0.32 log units. Division of the 210 compounds into a training set and a test set, each of 105 compounds, showed that the training equation could predict log P liver values with an average error of 0.05 and a standard deviation of 0.34 log units.
Drug Discovery Today, 2002
and H-bond acidity and H-bond basicity. These descriptors can be rapidly estimated from structure... more and H-bond acidity and H-bond basicity. These descriptors can be rapidly estimated from structure by a fragment scheme and used to predict physicochemical and transport properties of drug candidates (e.g. logP, solubility, gastrointestinal absorption, permeability and blood-brain distribution). The solvation equations can be interpreted to provide a qualitative chemical insight into biological partition and transport mechanisms. Applications to blood-brain partition and human intestinal absorption (HIA) are discussed.
Journal of Chromatography A, 2004
The use of gas-liquid chromatographic (GLC) retention data to obtain sets of solute descriptors i... more The use of gas-liquid chromatographic (GLC) retention data to obtain sets of solute descriptors is outlined, with reference to the schemes of Laffort and of Weckwerth. The method of Snyder and Dolan to obtain a set of solute descriptors from reverse phase high performance chromatographic (RP-HPLC) measurements is described. The work of Abraham on the construction of solvation parameters, or descriptors, from water-solvent partitions, GLC retention data and RP-HPLC data is considered in some detail. A comparison is made between the schemes of Laffort, Weckwerth and Abraham, and it is shown that the latter two yield exactly the same fits for a test data set of gas-methanol partition coefficients, although the distribution of chemical information amongst the terms in the multiple linear regressions is not quite the same. A comparison between the above 'experimental' descriptors and theoretical descriptors is made, and it is shown that the experimental Abraham and the theoretical Klamt descriptors encode almost the same chemical information. It is concluded that for processes that entail transfer of a solute from one phase to another, only a small number of solute descriptors, no more than five or six, is needed to provide a reasonably accurate analysis of the process.
International journal of pharmaceutics, 2007
Data on distribution coefficients from blood or plasma to rat skin and rabbit skin have been comp... more Data on distribution coefficients from blood or plasma to rat skin and rabbit skin have been compiled. From previous work on blood/plasma to brain or to muscle it is apparent that distributions from blood and plasma can be combined, and we show that it is possible to combine data on distribution to rat skin and rabbit skin. The combined set of blood/plasma distribution to rat and rabbit skin for 59 compounds, as logPskin, can be correlated through a linear free energy equation with a correlation coefficient of 0.856 and a standard deviation of 0.26 log units. The predictive capability of the equation has been assessed through training and test sets, and it is shown that the S.D. value of 0.26 log units is a good estimate of the predictive ability. The equation for logPskin has been compared to equations for a large number of possible model processes, using two mathematical methods. It is shown that there is no process amongst those we have examined that has any advantage over the pr...
Pest Management Science, 2013
The prediction of blood-tissue partitions, water-skin partitions and skin permeation for agrochem... more The prediction of blood-tissue partitions, water-skin partitions and skin permeation for agrochemicals.
Determination of sets of solute descriptors from chromatographic measurements
Journal of Chromatography A, 2004
The use of gas-liquid chromatographic (GLC) retention data to obtain sets of solute descriptors i... more The use of gas-liquid chromatographic (GLC) retention data to obtain sets of solute descriptors is outlined, with reference to the schemes of Laffort and of Weckwerth. The method of Snyder and Dolan to obtain a set of solute descriptors from reverse phase high performance chromatographic (RP-HPLC) measurements is described. The work of Abraham on the construction of solvation parameters, or descriptors, from water-solvent partitions, GLC retention data and RP-HPLC data is considered in some detail. A comparison is made between the schemes of Laffort, Weckwerth and Abraham, and it is shown that the latter two yield exactly the same fits for a test data set of gas-methanol partition coefficients, although the distribution of chemical information amongst the terms in the multiple linear regressions is not quite the same. A comparison between the above 'experimental' descriptors and theoretical descriptors is made, and it is shown that the experimental Abraham and the theoretical Klamt descriptors encode almost the same chemical information. It is concluded that for processes that entail transfer of a solute from one phase to another, only a small number of solute descriptors, no more than five or six, is needed to provide a reasonably accurate analysis of the process.
Distribution coefficients, Kbi00d and KtiSSues (or biophase), from the gas phase to blood and gas... more Distribution coefficients, Kbi00d and KtiSSues (or biophase), from the gas phase to blood and gas phase to tissues (plasma, brain, fat, heart, liver, lung, kidney, muscle, urine, saline and olive oil) have been collected for large number of volatile organic compounds (VOCs). For these datasets of VOCs, linear free energy relationships (LFERs) have been established and Abraham equations have successfully been constructed to predict these distributions. It has also been shown that human and rat data for the air to blood and air to tissue distribution of VOCs can be combined. The differences in the two data sets, for the common compounds are smaller than the estimated inter-laboratory experimental error. The combination of the log KtiSSue values with values for air to blood yields distribution coefficients from blood to tissue, as log PtiSSue-Equations have successfully been constructed to predict these distributions. From a large amount of collected data on the distribution of drugs f...
Drug Discovery Today, 2002
and H-bond acidity and H-bond basicity. These descriptors can be rapidly estimated from structure... more and H-bond acidity and H-bond basicity. These descriptors can be rapidly estimated from structure by a fragment scheme and used to predict physicochemical and transport properties of drug candidates (e.g. logP, solubility, gastrointestinal absorption, permeability and blood-brain distribution). The solvation equations can be interpreted to provide a qualitative chemical insight into biological partition and transport mechanisms. Applications to blood-brain partition and human intestinal absorption (HIA) are discussed.
Air to Muscle and Blood/Plasma to Muscle Distribution of Volatile Organic Compounds and Drugs: Linear Free Energy Analyses
Chemical Research in Toxicology, 2006
Distribution coefficients, K(mus), from the gas phase to the muscle have been collected for volat... more Distribution coefficients, K(mus), from the gas phase to the muscle have been collected for volatile organic compounds (VOCs). For 114 VOCs, a linear free energy relationship (LFER) yields an equation for log K(mus) with R(2) = 0.944 and SD = 0.267; construction of a training and test set shows that the LFER can predict further values to around 0.30 log units. The combination of the log K(mus) values with values for air to blood yields distribution coefficients from blood to muscle, log P(mus), for 110 VOCs; the corresponding LFER has R(2) = 0.537 and SD = 0.207 and a predictive capability of 0.22 log units. We also collected data on the distribution of drugs from blood or plasma to muscle and showed that the two sets of data can be combined. A LFER for blood/plasma to muscle for 59 drugs has R(2) = 0.745 and SD = 0.253 and a predictive capability of 0.25 log units. Finally, we show that the in vitro data on VOCs and the in vivo data on drugs can be combined; a LFER on the total data for 163 compounds has R(2) = 0.595, SD = 0.220, and a predictive capability of about 0.25 log units.
European Journal of Medicinal Chemistry, 2006
Partition coefficients, Kfat, from air to human fat and to rat fat have been collected for 129 vo... more Partition coefficients, Kfat, from air to human fat and to rat fat have been collected for 129 volatile organic compounds, VOCs. A linear free energy relationship, LFER, correlates the 129 values of logKfat with R2=0.958 and a standard deviation, S.D., of 0.194 log units. Use of training and test sets gives a predictive assessment of around 0.20 log units. Combination
Chemical Research in Toxicology, 2005
Partition coefficients, K blood , for volatile organic compounds from air to blood have been coll... more Partition coefficients, K blood , for volatile organic compounds from air to blood have been collected for 155 compounds (air to human blood) and 127 compounds (air to rat blood). For 86 common compounds, the average error, AE, between the two sets of log K blood values is 0.12 log units, somewhat smaller than our estimated interlaboratory average SD value of around 0.16 log units. We conclude that with regard to experimental errors, there is no significant difference between K blood values in human blood and in rat blood. There are 196 compounds for which either or both K blood (human) and K blood (rat) are available. A training set of 98 compounds could be fitted with the Abraham solvation parameters with R 2 ) 0.933 and SD ) 0.34 log units. The training equation was then used to predict the test set of values with AE ) 0.04 log units, SD ) 0.33 log units, and an average absolute error, AAE, of 0.25 log units. A second training and test set yielded similar values: AE ) 0.01, SD ) 0.39, and AAE ) 0.29 log units. It is concluded that it is possible to construct an equation capable of predicting further values of log K blood to around 0.30 log units. Because the descriptors used in the correlation equations can be predicted from structure, it is now possible to predict log K blood for any chemical structure.
Journal of Chemical Information and Modeling, 2006
Literature values of gas to olive oil partition coefficients at 37°C have been assembled for 218 ... more Literature values of gas to olive oil partition coefficients at 37°C have been assembled for 218 compounds. Application of an Abraham linear free energy equation correlates 215 compounds with R 2 ) 0.981 and a standard deviation, SD, of 0.196 log units. One hundred and eight compounds were then used as a training set, and the resulting equation was used to predict the remaining 107 compounds with an average error of 0.025, an absolute average error of 0.150, and a standard deviation of 0.224 log units. The linear free energy equation shows that as a solvent olive oil is not very polar but is reasonably basic, although with a weaker hydrogen bond base than ethyl acetate or acetone, and has no hydrogen bond acidity. The coefficients for partition from the gas phase to biological phases such as blood and brain lie between those for water and olive oil, which explains why gas to biological phase partition can be described in an empirical way by a combination of gas to olive oil and gas to saline coefficients
Partition of compounds from gas to water and from gas to physiological saline at 310 K: Linear free energy relationships
Fluid Phase Equilibria, 2007
Data have been assembled on gas to water partition coefficients for 374 compounds at 310K. It is ... more Data have been assembled on gas to water partition coefficients for 374 compounds at 310K. It is shown that an Abraham solvation equation with five descriptors can be used to correlate 350 such values, as logKW(310), with R2=0.994 and S.D.=0.154log units. Division into a training set and a test set shows that there is no bias in predictions and that
A simple method for estimating in vitro air-tissue and in vivo blood-tissue partition coefficients
Chemosphere, 2015
A simple method is reported for the estimation of in vivo air-tissue partition coefficients of VO... more A simple method is reported for the estimation of in vivo air-tissue partition coefficients of VOCs and of in vitro blood-tissue partition coefficients for volatile organic compounds and other compounds. Linear free energy relationships for tissues such as brain, muscle, liver, lung, kidney, heart, skin and fat are available and once the Abraham descriptors are known for a compound, no more than simple arithmetic is required to estimate air-tissue and blood-tissue partitions.
Journal of Pharmaceutical Sciences, 2006
Literature values of the in vivo distribution (BB) of drugs from blood, plasma, or serum to rat b... more Literature values of the in vivo distribution (BB) of drugs from blood, plasma, or serum to rat brain have been assembled for 207 compounds (233 data points). We find that data on in vivo distribution from blood, plasma, and serum to rat brain can all be combined. Application of our general linear free energy relationship (LFER) to the 207 compounds yields an equation in log BB, with R 2 ¼ 0.75 and a standard deviation, SD, of 0.33 log units. An equation for a training set predicts the test set of data with a standard deviation of 0.31 log units. We further find that the in vivo data cannot simply be combined with in vitro data on volatile organic and inorganic compounds, because there is a systematic difference between the two sets of data. Use of an indicator variable allows the two sets to be combined, leading to a LFER equation for 302 compounds (328 data points) with R 2 ¼ 0.75 and SD ¼ 0.30 log units. A training equation was then used to predict a test set with SD ¼ 0.25 log units. ß
Predicting Penetration Across the Blood-Brain Barrier from Simple Descriptors and Fragmentation Schemes
Journal of Chemical Information and Modeling, 2007
The ability to cross the blood brain barrier (BBB), sometimes expressed as BBB+ and BBB-, is a ve... more The ability to cross the blood brain barrier (BBB), sometimes expressed as BBB+ and BBB-, is a very important property in drug design. Several computational methods have been employed for the prediction of BBB-penetrating (BBB+) and nonpenetrating (BBB-) compounds with overall accuracies from 75 to 97%. However, most of these models use a large number of descriptors (67-199), and it is not easy to implement the models in order to predict values of BBB+/-. In this work, 19 simple molecular descriptors calculated from Algorithm Builder and fragmentation schemes were used for the analysis of 1593 BBB+/- data. The results show that hydrogen-bonding properties of compounds play a very important role in modeling BBB penetration. Several BBB models based on hydrogen-bonding properties, such as Abraham descriptors, polar surface area (PSA), and number of hydrogen bonding donors and acceptors, have been built using binomial-PLS analysis. The results show that the overall classification accuracy for a training set is over 90%, and overall prediction accuracy for a test set is over 95%.
European Journal of Medicinal Chemistry, 2008
Values of in vitro gas to lung partition coefficients, K lung , of VOCs have been collected from ... more Values of in vitro gas to lung partition coefficients, K lung , of VOCs have been collected from the literature. For 44 VOCs, application of the Abraham solvation equation to log K lung yielded a correlation with R 2 ¼ 0.968 and S.D. ¼ 0.25 log units. Combination of the log K lung values with log K blood values leads to in vitro blood to lung partition coefficients, log P lung for 43 VOCs; an Abraham solvation equation correlated these values with a very poor R 2 ¼ 0.262 but with a very good S.D. ¼ 0.190 log units.
European Journal of Medicinal Chemistry, 2006
Partition coefficients, K brain , for volatile organic compounds, VOCs, from air to brain have be... more Partition coefficients, K brain , for volatile organic compounds, VOCs, from air to brain have been collected for 81 compounds (air to human brain and air to rat brain). For the 81 VOCs a linear free energy equation (LFER) correlates log K brain with R 2 = 0.923 and S.D. = 0.346 log units. Use of training and test sets gives a predictive assessment of 0.35-0.40 log units. Combination of log K brain with our previously listed values of log K blood enables blood to brain partition, as log P b-brain , to be obtained for 78 VOCs. These values can be correlated with R 2 = 0.725 and S.D. = 0.203 log units; use of training and test sets allows a predictive assessment for log P b-brain of 0.16-0.20 log units. Values for air to plasma were available for 21 VOCs. When these data were combined with the data on air to blood and air to brain, values for partition between (blood or plasma) to brain, P bp-brain , were available for 99 VOCs. A LFER correlates this data with R 2 = 0.703 and S.D. = 0.197 log units; use of training and test sets allows a predictive assessment for log P bp-brain of 0.15-0.20 log units.
European Journal of Medicinal Chemistry, 2007
Values of in vitro air to liver partition coefficients, K liver , of VOCs have been collected fro... more Values of in vitro air to liver partition coefficients, K liver , of VOCs have been collected from the literature. For 124 VOCs, application of the Abraham solvation equation to log K liver yielded a correlation equation with R 2 ¼ 0.927 and SD ¼ 0.26 log units. Combination of the log K liver values with log K blood values leads to in vitro blood to liver partition coefficients, as log P liver for VOCs; an Abraham solvation equation can correlate 125 such values with R 2 ¼ 0.583 and SD ¼ 0.23 log units. Values of in vivo log P liver for 85 drugs were collected, and were correlated with R 2 ¼ 0.522 and SD ¼ 0.42 log units. When the log P liver values for VOCs and drugs were combined, an Abraham solvation equation could correlate the 210 compounds with R 2 ¼ 0.544 and SD ¼ 0.32 log units. Division of the 210 compounds into a training set and a test set, each of 105 compounds, showed that the training equation could predict log P liver values with an average error of 0.05 and a standard deviation of 0.34 log units.
Drug Discovery Today, 2002
and H-bond acidity and H-bond basicity. These descriptors can be rapidly estimated from structure... more and H-bond acidity and H-bond basicity. These descriptors can be rapidly estimated from structure by a fragment scheme and used to predict physicochemical and transport properties of drug candidates (e.g. logP, solubility, gastrointestinal absorption, permeability and blood-brain distribution). The solvation equations can be interpreted to provide a qualitative chemical insight into biological partition and transport mechanisms. Applications to blood-brain partition and human intestinal absorption (HIA) are discussed.
Journal of Chromatography A, 2004
The use of gas-liquid chromatographic (GLC) retention data to obtain sets of solute descriptors i... more The use of gas-liquid chromatographic (GLC) retention data to obtain sets of solute descriptors is outlined, with reference to the schemes of Laffort and of Weckwerth. The method of Snyder and Dolan to obtain a set of solute descriptors from reverse phase high performance chromatographic (RP-HPLC) measurements is described. The work of Abraham on the construction of solvation parameters, or descriptors, from water-solvent partitions, GLC retention data and RP-HPLC data is considered in some detail. A comparison is made between the schemes of Laffort, Weckwerth and Abraham, and it is shown that the latter two yield exactly the same fits for a test data set of gas-methanol partition coefficients, although the distribution of chemical information amongst the terms in the multiple linear regressions is not quite the same. A comparison between the above 'experimental' descriptors and theoretical descriptors is made, and it is shown that the experimental Abraham and the theoretical Klamt descriptors encode almost the same chemical information. It is concluded that for processes that entail transfer of a solute from one phase to another, only a small number of solute descriptors, no more than five or six, is needed to provide a reasonably accurate analysis of the process.