Klara Valko

Klara Valko
University College London | UCL · School of Pharmacy

Ph D, D Sc

About

128
Publications
18,884
Reads
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4,504
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Introduction
Additional affiliations
March 2016 - present
Bio-Mimetic Chromatography Consultancy
Position
  • Research Director
Description
  • Providing consultancy on setting up biomimetic HPLC measurements and applications f the measured data in drug discovery.
September 2003 - present
University College London
Position
  • Professor
Description
  • I teach the Physchem/ADME module for Drug Discovery Msc students.
September 2002 - March 2016
GlaxoSmithKline plc. Stevenage, Herts. UK
Position
  • Senior Research Investigator
Education
September 1972 - February 1977
Semmelweis University
Field of study
  • School of Pharmacy

Publications

Publications (128)
Article
Biomimetic chromatography is the name of the High Performance Liquid Chromatography (HPLC) methods that apply stationary phases containing proteins and phospholipids that can mimic the biological environment where drug molecules distribute. The applied mobile phases are aqueous organic with a pH of 7.4 to imitate physiological conditions that would...
Article
The potential of biomimetic chromatography to predict ecotoxicological endpoints of pharmaceutical compounds was investigated. For this purpose, a data set of previously and newly measured chromatographic retention data for 36 structurally diverse drugs was used. Standardized retention times were measured on immobilized artificial membrane, human s...
Article
Full-text available
The major causes of failure of drug discovery compounds in clinics are the lack of efficacy and toxicity. To reduce late-stage failures in the drug discovery process, it is essential to estimate early the probability of adverse effects and potential toxicity. Cardiotoxicity is one of the most often observed problems related to a compound's inhibiti...
Article
Full-text available
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...
Article
Full-text available
p class="ADMETabstracttext">Immobilized Artificial Membrane (IAM) chromatography columns have been used to model the in vivo distribution of drug discovery compounds. Regis Technologies Inc., the manufacturer, had to replace the silica support and consequently introduced a new IAM.PC.DD2 column that shows slightly different selectivity towards acid...
Chapter
This chapter describes the application of various separation methods for the measurements of physicochemical and biomimetic properties of early drug discovery compounds. The retention on reversed-phase stationary phases is proportional to the lipophilicity, while the retention using chemically bonded protein stationary phases and immobilized artifi...
Chapter
Thin-layer chromatography (TLC) will continue to play a basic role in determining the separation possibilities of chromatographic methods for the routine analysis of large numbers of samples or to analyze samples in cases where high-performance liquid chromatography has difficulties. TLC has the advantage that it does not require sophisticated and...
Article
Full-text available
Three promising antibacterial peptides were studied with regard to their ability to inhibit the growth and kill the cells of clinical strains of Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium. The multifunctional gramicidin S (GS) was the most potent, compared to the membranotropic temporin L (TL), being more effective than t...
Article
Full-text available
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 p...
Chapter
Amyotrophic lateral sclerosis (ALS) is caused by selective and progressive loss of spinal, bulbar and cortical motoneurons and leads to irreversible paralysis, loss of speech, inability to swallow and respiratory malfunctions with the eventual death of the affected individual in a rapid disease course. Several suggested molecular pathways are revie...
Article
Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Sunitinib, a multikinase inhibitor, was the first Fms-like tyrosine kinase 3 (FLT3) inhibitor clinically used against AML. Off-target effects are a major concern for multikinase inhibitors. As targeted delivery may reduce such undesired side effects, our goal was to develop...
Article
Full-text available
div>The authors of the original paper published with the same title: ADMET & DMPK 5(1) (2017) 14-38; doi: 10.5599/admet.5.1.373, apologize for the error in the plot on Figure 5. The erratum gives a correct plot. </div
Article
Full-text available
p class="ADMETabstracttext">Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease of the human motor system. Subunits of the 33-amino acid containing motorneurontrophic factor (MNTF) have been investigated and GM6 has been found as a potential peptide therapeutic for ALS. This linear peptide drug candidate has been c...
Article
Full-text available
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 in v...
Article
Full-text available
p class="ADMETabstracttext">Peptide therapeutics are new modalities offering several challenges to drug discovery. They are generally less stable and permeable in vivo. The characterization of their lipophilicity cannot be carried out using the traditional in silico or wet octanol/water partition coefficients. The prediction of their in vivo distri...
Article
Full-text available
The drug discovery process can be accelerated by chromatographic profiling of analogs by measuring their nonspecific binding to proteins and lipids and then by modeling in vivo distribution. A balanced potency and chromatographically determined membrane and protein binding ensure the selection of compounds with the highest probability to show the d...
Preprint
Full-text available
The high performance liquid chromatography (HPLC) measurements of the biomimetic properties of drug discovery compounds has been described and reviewed in the previous article (1). The property measurements are based on calibrated generic gradient retention times obtained on C18, human serum albumin (HSA), alpha-1-acid-glycoprotein (AGP), and immob...
Article
Full-text available
The biomimetic gradient retention time measurements on C18, immobilized artificial membrane (IAM), human serum albumin (HSA), and acid-glycoprotein (AGP) stationary phases can be used to characterize compounds partitioning into phospholipids and proteins. The data obtained can then be used in equations to estimate the in vivo plasmaÐtissue distribu...
Article
Full-text available
The drug discovery process can be accelerated by chromatographic profiling of analogs by measuring their nonspecific binding to proteins and lipids and then by modelling in vivo distribution. A balanced potency and chromatographically determined membrane and protein binding ensure the selection of compounds with the highest probability to show the...
Article
Full-text available
p class="ADMETabstracttext">The drug discovery process can be accelerated by chromatographic profiling of the analogs to model in vivo distribution and the major non-specific binding. A balanced potency and chromatographically determined membrane and protein binding (IAM MB/PB) data enable selecting drug discovery compounds for further analysis tha...
Article
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...
Article
Full-text available
The ability to explain distribution patterns from drug physicochemical properties and binding characteristics has been explored for more than 200 compounds by interrogating data from quantitative whole body autoradiography studies (QWBA). These in vivo outcomes have been compared to in silico and in vitro drug property data to determine the most in...
Article
One of the key challenges facing early stage drug discovery is understanding the commonly observed difference between the activity of compounds in biochemical assays and cellular assays. Traditionally, indirect or estimated cell permeability measurements such as estimations from logP or artificial membrane permeability are used to explain the diffe...
Data
Full-text available
Table S1. Summarizing rat tissue distribution data from excretion and metabolism studies conducted at GSK using radioactive drug analogs for 46 molecules. Table S2. Comparing tissue distribution from QWBA studies (in terms of tissue: blood AUC ratios) to drug property data for >200 structurally unrelated molecules.
Article
The hybridisation of hits, identified by complementary fragment and high throughput screens, enabled the discovery of the first series of potent inhibitors of mitochondrial branched-chain aminotransferase (BCATm), based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth enabled rapid optimisation of acti...
Book
Based on a course taught by the author for many years, this book demonstrates how to use chromatography to measure the physicochemical and biomimetic properties of drug candidates in the early stages of drug discovery in order to fully optimize drug leads. Readers will learn how to interpret chromatographic retention data using various models in or...
Data
Full-text available
Article
Introduction: Complex physicochemical and biological processes influence the oral absorption of a drug molecule. Consideration of these processes is an important activity during the optimisation of potential candidate molecules. Areas covered: The authors review the applications of physicochemical and structural requirements for intestinal absor...
Article
The concepts of drug efficiency (D(eff) ) and Drug Efficiency Index (DEI) have been recently introduced as useful parameters to optimize the absorption, distribution, metabolism, elimination/excretion, and toxicity properties and in vivo efficacy potential of molecules during lead optimization and at pre-clinical stages. The available free drug con...
Article
Macrolides are stereospecific macrolactones of high molecular weights. Herein, 600 mostly semisynthetic macrolides are compared with 50,000 small non-macrolide synthetic molecules in terms of measured physicochemical properties in order to assess the drug-likeness and developability chances of macrolides. The pre-selected set of diverse macrolides...
Article
Introduction: The ultimate objective of optimizing adsorption, distribution, metabolism and excretion (ADME) parameters in drug discovery is to maximize the unbound concentration at the site of action for a given dose level. This has the added benefit of minimizing the efficacious dose, reducing the potential for attrition related to drug burden a...
Article
Full-text available
The in vivo unbound volume of distribution (V(du)) can be used to estimate the free steady-state plasma concentration with a given dose of a drug administered intravenously. We have demonstrated that the calibrated HPLC retention times obtained on biomimetic stationary phases, such as immobilised human serum albumin and phosphatidyl-choline, can be...
Article
Macrolides with 14- and 15-membered ring are characterized by high and extensive tissue distribution, as well as good cellular accumulation and retention. Since macrolide structures do not fit the Lipinski rule of five, macrolide pharmacokinetic properties cannot be successfully predicted by common models based on data for small molecules. Here we...
Article
Full-text available
A major concern for the pharmaceutical industry is the high attrition rate (>90 per cent) of potential drug molecules failing during late stages of the drug discovery process. This may be due to lack of efficacy in the clinic, unexpected side effects or unfavourable pharmacokinetics. There is a need for new tools to predict the in vivo distribution...
Article
Modification of the benzo rings of 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones into heteroaromatic systems was investigated to enhance physicochemical properties and potency profile of this class of inhibitors. The synthesis and biological activity of the derived compounds is discussed.
Article
Full-text available
A validated reversed-phase thin-layer chromatographic (RPTLC) method is proposed for parallel estimation of the lipophilicity of chemically diverse neutral compounds or weak acids and bases. To cover a wide range of lipophilicity two optimized chromatographic systems were used - one for determination of log P of low or moderately lipophilic compoun...
Article
Full-text available
The linear solvation equation approach has been used to describe the octanol/water lipophilicity scale (logPoct) and the isocratic retention factors (log k) obtained using reversed phase HPLC with acetonitrile. Both the octanol/water partition coefficients and the RP-HPLC retention data obtained from the literature, showed good correlation with the...
Article
Lipophilicity is an important property in assessing the developability of a drug candidate. HPLC provides a reliable and automated method for determining lipophilicity based on retention times. Stationary phase ligands and mobile phase conditions can be varied to probe drug properties such as plasma protein binding, phospholipid binding, and volume...
Article
The volume of distribution (VD) in humans of 179 known drug molecules (acids, bases, and neutrals) has been modeled using two biomimetic-binding measurements. The phospholipid binding (log K (IAM)) and the plasma protein binding (log K (HSA)) have been calculated from gradient HPLC retention times on immobilized artificial membrane (IAM) and on hum...
Article
Full-text available
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 reso...
Article
A short, efficient, and highly stereoselective synthesis of a series of (3R,6R,7R)-2,5-diketopiperazine oxytocin antagonists and their pharmacokinetics in rat and dog is described. Prediction of the estimated human oral absorption (EHOA) using measured lipophilicity (CHI log D) and calculated size (cMR) has allowed us to rank various 2,5-diketopipe...
Article
Full-text available
During drug discovery, it is important to optimise the affinity for the biomolecular target and also the properties of molecules that influence absorption, distribution, metabolism, excretion, and toxicity (ADMET). The goal is to improve the properties of a lead compound and select highly ‘developable’ candidates. Efficient pharmaceutical property...
Article
Octanol-water partition coefficients are the most widely used measure of lipophilicity in modelling biological partition/distribution. It has long been recognised that the retention of a compound in reversed-phase liquid chromatography is governed by its lipophilicity/hydrophobicity, and thus shows correlation with an octanol-water partition coeffi...
Article
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 HSA binding values were derived from the gradient retention times that were converted to the logarithm of the equilibrium constants (logK HSA) using data from...
Article
Full-text available
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 t...
Article
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 value...
Article
Full-text available
Solvation equations have been obtained for seven high performance liquid chromatographic (HPLC) systems, generated in the reverse phase (RP) mode with fast gradient elution. A training set of 40 compounds was used for each system. The seven equations were then used to calculate Abraham descriptors for a completely separate 40-compound test set. In...
Article
The linear-solvent strength (LSS) model of gradient elution has been applied to estimate parameters of lipophilicity and acidity of a series of drugs and model chemicals. Apparent pKa values and log kw values for individual analytes were determined in 2-3 gradient runs. The first experiment (or first two experiments) uses a wide-range organic modif...
Article
We have shown previously that using a trifluoroethanol containing mobile phase provides a unique chromatographic selectivity. This is essential to derive molecular descriptors by HPLC which requires retention data from several systems. It also requires that the ionisation is suppressed so that retention times reflect the properties of the neutral m...
Article
The selectivity of Luna C18 Xterra C18 and Fluophase (perfluorinated C6) stationary phases has been investigated with aqueous acetonitrile, methanol and 2,2,2-trifluoroethanol mobile phases using linear solvation equations. The gradient retention times of a set of 60 compounds with known molecular descriptors have been determined. Linear solvation...
Article
The relationships between retention and mobile-phase pH in gradient elution are studied for acids and bases. The apparent pH shift caused by the increasing amount of acetonitrile and methanol has been determined starting from a wide range of pH values. It is shown that good relationships between the retention of ionizable compounds and the pH of th...
Article
We propose a rapid method for the measurement of octanol/water partition coefficients (log Poct) 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 g...
Article
We propose a rapid method for the measurement of octanol / water partition Coefficients (log Poct) 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...
Chapter
With the emergence of combinatorial chemistry in drug discovery the measurement of physico-chemical parameters for a large number of compounds is required at a much earlier stage of the drug discovery process. The most important physical–chemical parameters are lipophilicity, solubility, acid–base character, and electrochemical redox potential. The...
Article
Full-text available
Retention data for a set of 69 compounds using rapid gradient elution are obtained on a wide range of reversed-phase stationary phases and organic modifiers. The chromatographic stationary phases studied are Inertsil (IN)-ODS, pentafluorophenyl, fluoro-octyl, n-propylcyano, Polymer (PLRP-S 100), and hexylphenyl. The organic solvent modifiers are 2,...
Article
A fast-gradient high-performance liquid chromatographic (HPLC) method has been suggested to characterize the interactions of drugs with an immobilized artificial membrane (IAM). With a set of standards, the gradient retention times can be converted to Chromatographic Hydrophobicity Index values referring to IAM chromatography (CHI(IAM)) that approx...
Article
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-...
Article
Thin-layer chromatography has always been a simple and relatively inexpensive method. It is widely used because of several advantages - for example, either several spots can be separated in parallel or two-dimensional separation can be easily performed; specific and sensitive color reagents enable detection of, and sometimes distinction between, se...
Article
The chromatographic hydrophobicity index (CHI) obtained from high-throughput gradient elution reversed-phase HPLC with ODS column and acetonitrile mobile phase has been shown to be well correlated with log k values obtained by isocratic elution in the same system; between CHI and log k50, the correlation coefficient was 0.99 for a very diverse set...
Article
Recently proposed chromatographic hydrophobicity indices (CHIs) have been calculated from the correlation of fast gradient HPLC retention times with ϕ0 values from isocratic HPLC measurements for 30 oligopeptide derivatives. Measurements were performed on five HPLC columns; an Inertsil ODS (In), a Prodigy ODS (Pro), an immobilised artificial membra...
Article
The solvation equation [Eq. (1)] can be applied to reversed-phase HPLC capacity factors (i.e. log SP=log k).(1)SP is a solute property (e.g., solubility or partition coefficient) and the explanatory variables are solute descriptors as follows: R2 is an excess molar refraction, π2H is the solute dipolarity/dipolarisability, Σα2H and Σβ2H are the sol...
Article
A new chromatographic hydrophobicity index (CHI) is described which can be used as part of a protocol for high-throughput (50-100 compounds/day) physicochemical property profiling for rational drug design. The index is derived from retention times (t(R)) observed in a fast gradient reversed-phase HPLC method. The isocratic retention factors (log k'...
Article
The protonated molecular ion intensities of 15 nucleosides obtained by thermospray ionisation have been measured using 0.1 M ammonium acetate mobile phase at neutral and acidic pH. To explain the dependence of the molecular ion intensity on the mobile phase pH, the hydrophobicity, the pKa values and reversed-phase high-performance liquid chromatogr...
Article
The binding properties of six indolocarbazole derivative have been measured using immobilised human serum albumin (HSA) in an HPLC column. The compounds showed very strong binding to HSA which necessitated the application of a 30 to 40% concentration of 2-propanol in the mobile phase. This represents a much higher concentration than is recommended...
Article
This chapter discusses the retention prediction of pharmaceutical compounds. It focuses on those pharmaceutical compounds that are structurally unrelated. The retention prediction is most widely applied is reversed-phase high-performance liquid chromatography (HPLC). Several approaches for retention predictions are known. The most widespread measur...
Article
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′) ag...
Article
An analytical method has been developed for the detection of trace amounts of impurities in 3′-azido-3′-deoxythymidine referred to herein as AZT (Zidovudine). A sample extract was preconcentrated by normal-phase high-performance liquid chromatography (HPLC) with subsequent on-line reversed-phase HPLC-thermospray mass spectrometry (TSP-MS). During t...