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- Leaving GSK after 22 years of service, now I am the founder director of Bio-Mimetic Chromatography Ltd providing data... moreLeaving GSK after 22 years of service, now I am the founder director of Bio-Mimetic Chromatography Ltd providing data analysis, biomimetic HPLC method set up and measurements, in vivo drug distribution modelling and various courses to pharmaceutical companies and manufacturers of analytical equipment. I am also an Honorary Professor at UCL School of Pharmacy since 2004 teaching the ADME module of the Drug Discovery and Pharma Management master's course. Founder of Bio-Mimetic Cosmetics that manufactures the Klaraskincare products.edit
Chloroquine and hydroxy-chloroquine already established as anti-malarial and lupus drugs have recently gained renewed attention in the fight against the Covid-19 pandemic. Bio-mimetic HPLC methods have been used to measure the protein and... more
Chloroquine and hydroxy-chloroquine already established as anti-malarial and lupus drugs have recently gained renewed attention in the fight against the Covid-19 pandemic. Bio-mimetic HPLC methods have been used to measure the protein and phospholipid binding of the racemic mixtures of the drugs. The tissue binding and volume of distribution of the enantiomers have been estimated. The enantiomers can be separated using Chiralpak AGP HPLC columns. From the α-1-acid-glycoprotein (AGP) binding, the lung tissue binding can be estimated for the enantiomers. The drugs have a large volume of distribution, showed strong and stereoselective glycoprotein binding, medium-strong phospholipid-binding indicating only moderate phospholipidotic potential, hERG inhibition and promiscuous binding. The drug efficiency of the compounds was estimated to be greater than 2 % which indicates a high level of free biophase concentration relative to dose. The biomimetic properties of the compounds support the...
Characterizing the properties of large numbers of compounds and estimating their potential absorption, distribution, metabolism and elimination properties are important early stages in the process of drug discovery and help to reduce... more
Characterizing the properties of large numbers of compounds and estimating their potential absorption, distribution, metabolism and elimination properties are important early stages in the process of drug discovery and help to reduce later stage attrition. The chromatographic separation principles using stationary phases that contain proteins and phospholipids are more suitable for compound characterization and estimation of the pharmacokinetic properties than the traditional octanol/water partition coefficient. This technology, when standardized, enables the prediction of in vivo behavior and the selection of compounds with the best potential, thus reducing the number of animal experiments. Chromatography may be involved more widely in the future to measure kinetic aspects of compounds’ binding to proteins and receptors which would enable designing compounds that require a lower frequency of doses and have more predictable pharmacokinetic profiles.
The drug discovery process usually involves the discovery of a potent new chemical entity which has shown some activity on a target that is believed to be relevant in a certain type of disease. However, the structure and property of these... more
The drug discovery process usually involves the discovery of a potent new chemical entity which has shown some activity on a target that is believed to be relevant in a certain type of disease. However, the structure and property of these putative drug molecules may have to be modified in order to ensure that they are able to exert the desired <em>in vivo</em> pharmacological effect. The candidate molecules usually have to be absorbed from the gastrointestinal system and therefore they must show appropriate solubility and permeability to be able to reach the target enzyme…
An alternative approach has been developed to estimate the clinical dose of new drug molecules at an early stage in the drug discovery process. This approach has been compared to traditional methods using the clinical dose as indicated on... more
An alternative approach has been developed to estimate the clinical dose of new drug molecules at an early stage in the drug discovery process. This approach has been compared to traditional methods using the clinical dose as indicated on the drug label of 136 marketed drugs. At the early stages of drug discovery only in silico predictions or some initial in vitro screening data are normally available, typically parameters such as affinity/potency (pXC50)from isolated enzymes or receptors, measured albumin and phospholipid binding using biomimetic HPLC measurements, and in vitro clearance using P450 enzymes or liver microsomes. The combination of the biomimetic HPLC phospholipid and protein binding provides a drug efficiency max parameter described previously (HPLC DE), and in vitro potency makes it possible to estimate a clinical dose that would result in an efficacious steady state free concentration at the site of action. The influence of the potential discrepancies between the in vitro and a later stage in vivo DE, the whole blood potency, volume of distribution and clearance on the dose estimation has been investigated, using data from a GSK programme profiled during lead optimisation. It was found that drug potency had the greatest influence on estimating the clinical dose. When the estimated dose is low, the impact of other parameters such as the volume of distribution and clearance was much less significant and typically did not affect compound ranking.
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HPLC methods that use chromatographic retention times for gaining information about the properties of compounds for the purpose of designing drug molecules are reviewed. Properties, such as lipophilicity, protein binding, phospholipid... more
HPLC methods that use chromatographic retention times for gaining information about the properties of compounds for the purpose of designing drug molecules are reviewed. Properties, such as lipophilicity, protein binding, phospholipid binding, and acid/base character can be incorporated in the design of molecules with the right biological distribution and pharmacokinetic profile to become an effective drug. Standardization of various methodologies is suggested in order to obtain data suitable for inter-laboratory comparison. The published HPLC methods for lipophilicity, acid/base character, protein and phospholipid binding are critically reviewed and compared with each other using the solvation equation approach. One of the most important discussion points is how these data can be used in models and how they can influence the drug discovery process. Therefore, the published models for volume of distribution, unbound volume of distribution and drug efficiency are also discussed. The general relationships between the chemical structure and biomimetic HPLC properties are described in view of ranking and selecting putative drug molecules.
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The influence of the operating parameters in capillary zone electrophoresis (CZE) on the separation of a human alpha-interferon has been investigated. The separation was characterised by the electrophoretic mobility of the first and last... more
The influence of the operating parameters in capillary zone electrophoresis (CZE) on the separation of a human alpha-interferon has been investigated. The separation was characterised by the electrophoretic mobility of the first and last observed peaks, and the number of peaks on the electropherogram, whether visible as shoulders or adequately resolved. No peaks could be observed at lower pH values
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Hydrophobic properties of 17 aniline and phenol derivatives were characterized by reversed-phase thin-layer chromatographic and high performance liquid chromatographic retention data.In order to elucidate the role of thin-layer... more
Hydrophobic properties of 17 aniline and phenol derivatives were characterized by reversed-phase thin-layer chromatographic and high performance liquid chromatographic retention data.In order to elucidate the role of thin-layer chromatographic supports in the hydrophobicity determination paraffin coated silica, aluminium oxide, cellulose, diatomaceous earth and their mixtures were used. Water, water-methanol 7:3 and 1 M NaCl served as mobile phases. The retention data were analyzed by spectral mapping technique.The potency values differed from support to support proving that the composition of support has a deciding role in the hydrophobicity determination of aniline and phenol derivatives. The eluents did not influence considerably the potency order of supports.
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Research Interests: Organic Chemistry, Pharmaceutical Chemistry, In Vitro, Humans, Virus, and 15 moreDrug Design, Hepatitis C Virus, Quinolones, Genotype, Bioorganic and medicinal Chemistry, Biological activity, Structure activity Relationship, Protein Binding, Chemical Synthesis, Physicochemical Properties, Antiviral Agents, Molecular Structure, Hepacivirus, High protein, and Pharmacology and pharmaceutical sciences
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Phospholipidosis is a term commonly used to indicate a phospholipid storage disorder; in affected cells, phospholipids accumulate in lysosomes that acquire a multilamellar morphological appearance. Cationic amphiphilic drugs (CADs) are... more
Phospholipidosis is a term commonly used to indicate a phospholipid storage disorder; in affected cells, phospholipids accumulate in lysosomes that acquire a multilamellar morphological appearance. Cationic amphiphilic drugs (CADs) are suggested to induce phospholipidosis by direct interaction of xenobiotics with intracellular phospholipids or by the action of xenobiotics on the synthesis and metabolism of phospholipids. To date, electron microscopy (EM) represents the most reliable and the preferred method for the demonstration of phospholipidotic cell damage. Nevertheless, EM has a low throughput, it is expensive, and it is not suitable for screening purposes. We discuss here the assessment of the the phospholipidogenic potential of drugs using a cell culture-based model. In this test, intracellular phospholipids of treated U-937 cells (a human monocyte-derived cell line) were measured using the fluorescent probe Nile red. Eleven CADs reported to induce phospholipidosis in vivo an...
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The potential anti-cancer activity of triazines was characterized by the inhibition of the growth of L1210/R71 cells. The retention times for fifteen triazine derivatives were measured by high-performance liquid chromatography on octyl... more
The potential anti-cancer activity of triazines was characterized by the inhibition of the growth of L1210/R71 cells. The retention times for fifteen triazine derivatives were measured by high-performance liquid chromatography on octyl silica and silica gel columns. The slope and intercept values of the plot of the logarithmic capacity factor versus acetonitrile concentration were calculated from the reversed-phase retention measurements. The adsorption properties of the compounds were characterized by the retention data obtained on silica gel columns using high and low concentrations of ammonium salts in the hydro-organic mobile phase. The non-polar, non-polar unsaturated and polar surface areas, the surface energies, the dipole moments and the Van der Waals radii of the molecules were calculated from their chemical structures after energy minimization on the basis of molecular mechanics. Correlation analysis of these parameters showed that the inhibitory effect is dependent on the polar and non-polar surface areas of the molecules. The reversed-phase slope showed a significant correlation with the difference between the accessible and the total non-polar surface areas of the compounds, whereas the intercept values correlated with the non-polar accessible surface area. The adsorption properties of the triazines on silica gel cannot be described by the molecular parameters investigated here.
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We propose a rapid method for the measurement of octanol/water partition coefficients (log P(oct)) via fast gradient reversed phase retention and the calculation of the hydrogen bond acidity of the compounds. The cycle time of the generic... more
We propose a rapid method for the measurement of octanol/water partition coefficients (log P(oct)) via fast gradient reversed phase retention and the calculation of the hydrogen bond acidity of the compounds. The cycle time of the generic gradient HPLC method is 5 minutes. The general solvation equation obtained for the log Poct values and the fast gradient Chromatographic Hydrophobicity Indices with acetonitrile (CHI(ACN)) and methanol
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The interaction of reduced and oxidized glutathiones with the herbicides diquat and paraquat was studied by charge-transfer chromatography carried out on un-impregnated cellulose layers. Diquat and paraquat interact both with reduced and... more
The interaction of reduced and oxidized glutathiones with the herbicides diquat and paraquat was studied by charge-transfer chromatography carried out on un-impregnated cellulose layers. Diquat and paraquat interact both with reduced and oxidized glutathiones forming charge-transfer complexes. The interaction is of hydrophilic character in both cases. The formation of covalently bonded conjugates was not observed. The strength of interaction decreases
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Normal phase HPLC and OPTLC methods are described for the analysis of Hevizos (5-isopropyl-2&#39;-beta-deoxyuridine) and it&#39;s impurities. The eluent is 50% water saturated ethyl-acetate to which 0.5-1.5% methanol is added... more
Normal phase HPLC and OPTLC methods are described for the analysis of Hevizos (5-isopropyl-2&#39;-beta-deoxyuridine) and it&#39;s impurities. The eluent is 50% water saturated ethyl-acetate to which 0.5-1.5% methanol is added depending on the silica used. The water content is important as it practically eliminates tailing. The methods can also be used for the determination of 5-isopropyl-2&#39;-beta-deoxyuridine and it&#39;s impurities in Hevizos ointment after a simple extraction procedure. The OPTLC method uses a CHROMPRES 10 apparatus, aluminum backed HPTLC plates and the same eluent-system as the HPLC method. The reproducibility of the HPLC method (rel. st. dev.) is 0.8%, the correlation coefficient is &gt; 0.999 for the main component, while the impurities can be determined at the 0.1% level with a reproducibility of 20%, and a correlation coefficient of &gt; 0.997. The reproducibility of the OPTLC method (rel. st. dev.) is 4% for the main component, while for the impurities at the 0.5% level the reproducibility is 20%.
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Acyclovir and 18 of its esters have been investigated by systematic measurement of their reversed-phase high-performance liquid chromatographic retention using differing mobile phase compositions. The methanol content of the mobile phase... more
Acyclovir and 18 of its esters have been investigated by systematic measurement of their reversed-phase high-performance liquid chromatographic retention using differing mobile phase compositions. The methanol content of the mobile phase was varied between 5 and 95%. By linear least squares regression of the logarithmic retention factor (log k′) against methanol concentration, the slope (S)_and intercept (log k′0) of the
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The influence of the operating parameters in capillary zone electrophoresis (CZE) on the separation of a human alpha-interferon has been investigated. The separation was characterised by the electrophoretic mobility of the first and last... more
The influence of the operating parameters in capillary zone electrophoresis (CZE) on the separation of a human alpha-interferon has been investigated. The separation was characterised by the electrophoretic mobility of the first and last observed peaks, and the number of peaks on the electropherogram, whether visible as shoulders or adequately resolved. No peaks could be observed at lower pH values
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Hydrophobic properties of 17 aniline and phenol derivatives were characterized by reversed-phase thin-layer chromatographic and high performance liquid chromatographic retention data.In order to elucidate the role of thin-layer... more
Hydrophobic properties of 17 aniline and phenol derivatives were characterized by reversed-phase thin-layer chromatographic and high performance liquid chromatographic retention data.In order to elucidate the role of thin-layer chromatographic supports in the hydrophobicity determination paraffin coated silica, aluminium oxide, cellulose, diatomaceous earth and their mixtures were used. Water, water-methanol 7:3 and 1 M NaCl served as mobile phases. The retention data were analyzed by spectral mapping technique.The potency values differed from support to support proving that the composition of support has a deciding role in the hydrophobicity determination of aniline and phenol derivatives. The eluents did not influence considerably the potency order of supports.
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A fast gradient HPLC method (cycle time 15 min) has been developed to determine Human Serum Albumin (HSA) binding of discovery compounds using chemically bonded protein stationary phases. The 2- propanol concentration is increased from 0... more
A fast gradient HPLC method (cycle time 15 min) has been developed to determine Human Serum Albumin (HSA) binding of discovery compounds using chemically bonded protein stationary phases. The 2- propanol concentration is increased from 0 to 25% in 3 minutes, thus allowing strongly bond compounds to elute within the 15 minutes. The HSA binding values were derived from the logarithmic values of the gradient retention times that were converted to logarithm of the equilibrium constants (logK HSA) using a calibration set of molecules. The logK HSA values for the calibration set of molecules have been derived from literature values of the % plasma protein binding. The method is fully automated and it has been used for lead optimization in more than 20 projects. The obtained HSA binding data on more than 4000 compounds were suitable to set up global and project specific quantitative structure binding relationships that helped compound design in the early drug discovery settings. The method...
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An analytical method has been developed for the detection of trace amounts of the principal synthetic route indicative impurity in lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine). A sample extract was preconcentrated by... more
An analytical method has been developed for the detection of trace amounts of the principal synthetic route indicative impurity in lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine). A sample extract was preconcentrated by normal-phase high-performance liquid chromatography (HPLC) and analysed by subsequent on-line reversed-phase HPLC-thermospray mass spectrometry (TSP-MS). During the sample extraction and concentration step, carried out by semipreparative normal-phase chromatography, the preliminary separation of the impurity from the lamotrigine takes place. The organic solvent (dichloroethane-methanol, 90:10, v/v) is evaporated from the collected fraction and the material is redissolved in a smaller volume of the reversed-phase mobile phase. The collected fraction is then subjected to reversed-phase HPLC-TSP-MS. The influence of an ultrasonic extraction step has been examined. When the method was applied to lamotrigine tablets, a shake flask partitioning step using 1...