Generation of a set of simple, interpretable ADMET rules of thumb

A set of simple, consistent structure-property guides have been determined from an analysis of a number of key ADMET assays run within GSK: solubility, permeability, bioavailability, volume of distribution, plasma protein binding, CNS penetration, brain tissue binding, P-gp efflux, hERG inhibition, and cytochrome P450 1A2/2C9/2C19/2D6/3A4 inhibition. The rules have been formulated using molecular properties that chemists intuitively know how to alter in a molecule, namely, molecular weight, logP, and ionization state. The rules supplement the more predictive black-box models available to us by clearly illustrating the key underlying trends, which are in line with reports in the literature. It is clear from the analyses reported herein that almost all ADMET parameters deteriorate with either increasing molecular weight, logP, or both, with ionization state playing either a beneficial or detrimental affect depending on the parameter in question. This study re-emphasizes the need to focus on a lower molecular weight and logP area of physicochemical property space to obtain improved ADMET parameters.     

The influence of lipophilicity in drug discovery and design

Introduction: The role of lipophilicity in drug discovery and design is a critical one. Lipophilicity is a key physicochemical property that plays a crucial role in determining ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties and the overall suitability of drug candidates. There is increasing evidence to suggest that control of physicochemical properties such as lipophilicity, within a defined optimal range, can improve compound quality and the likelihood of therapeutic success.

Areas covered: This review focuses on understanding lipophilicity, techniques used to measure lipophilicity, and summarizes the importance of lipophilicity in drug discovery and development, including a discussion of its impact on individual ADMET parameters as well as its overall influence on the drug discovery and design process, specifically within the past 15 years.

Expert opinion: A current review of the literature reveals a continued reliance on the synthesis of novel structures with increased potency, rather than a focus on maintaining optimal physicochemical properties associated with ADMET throughout drug optimization. Particular attention to the optimum region of lipophilicity, as well as monitoring of lipophilic efficiency indices, may contribute significantly to the overall quality of candidate drugs at different stages of discovery.     

Estimation of permeability by passive diffusion through Caco-2 cell monolayers using the drugs'' lipophilicity and molecular weight

A recently developed, new theoretical absorption model for passive diffusion through biological membranes describing the dependency of membrane permeability on lipophilicity and molecular size, predicts different sigmoid–hyperbolic permeability–lipophilicity relationships for different molecular weight ranges. This model has been tested with experimental in vitro cultured epithelial cell (Caco-2) permeability data for structurally diverse drugs differing in lipophilicity, ionization state and molecular size. These data were pooled with literature values. Using this simple physicochemical approach, the permeability of a compound through Caco-2 cells by passive diffusion can be predicted from the compounds' distribution coefficient in 1-octanol/water (log D_oct) and its molecular weight (MW). Deviations from this expected behaviour may point to the involvement of biological components in the transport process, which may require further investigations.     

The influence of the 'organizational factor' on compound quality in drug discovery

Physicochemical properties such as lipophilicity and molecular mass are known to have an important influence on the absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of small-molecule drug candidates. To assess the use of this knowledge in reducing the likelihood of compound-related attrition, the molecular properties of compounds acting at specific drug targets described in patents from leading pharmaceutical companies during the 2000-2010 period were analysed. Over the past decade, there has been little overall change in properties that influence ADMET outcomes, but there are marked differences in molecular properties between organizations, which are maintained when the targets pursued are taken into account. The target-unbiased molecular property differences, which are attributable to divergent corporate drug design strategies, are comparable to the differences between the major drug target classes. On the basis of our analysis, we conclude that a substantial sector of the pharmaceutical industry has not modified its drug design practices and is still producing compounds with suboptimal physicochemical profiles.     

Machine learning approaches for predicting compounds that interact with therapeutic and ADMET related proteins

Computational methods for predicting compounds of specific pharmacodynamic and ADMET (absorption, distribution, metabolism, excretion and toxicity) property are useful for facilitating drug discovery and evaluation. Recently, machine learning methods such as neural networks and support vector machines have been explored for predicting inhibitors, antagonists, blockers, agonists, activators and substrates of proteins related to specific therapeutic and ADMET property. These methods are particularly useful for compounds of diverse structures to complement QSAR methods, and for cases of unavailable receptor 3D structure to complement structure-based methods. A number of studies have demonstrated the potential of these methods for predicting such compounds as substrates of P-glycoprotein and cytochrome P450 CYP isoenzymes, inhibitors of protein kinases and CYP isoenzymes, and agonists of serotonin receptor and estrogen receptor. This article is intended to review the strategies, current progresses and underlying difficulties in using machine learning methods for predicting these protein binders and as potential virtual screening tools. Algorithms for proper representation of the structural and physicochemical properties of compounds are also evaluated.     

Simple physicochemical properties related with lipophilicity,polarity, molecular size and ionization status exert significant impact on the transfer of drugs and chemicals into human breast milk

Objectives: The transfer of xenobiotic compounds into human breast milk has raised serious concerns in the last few years. The present study is aimed to assess whether simple physicochemical properties exert significant impact on human breast milk transfer of drugs and chemicals.

Methods: A large data set of 375 xenobiotic compounds with available experimental milk to plasma (M/P) ratios was systematically compiled from the literature and explored with their physicochemical properties being further analyzed with respect to their extent to transfer into breast milk.

Results: Xenobiotic compounds with increased breast milk transfer (M/P ≥ 1) were characterized by enhanced lipophilicity and decreased molecular size (p < 0.05). Enhanced polarity and hydrogen bonding capacity were more frequently observed in xenobiotic compounds with reduced breast milk transfer (p < 0.0001). Xenobiotic compounds presenting increased positive charge at pH 7.4 were characterized by enhanced breast milk transfer (p < 0.001). Xenobiotic compounds presenting increased negative charge at pH 7.4 were characterized by decreased breast milk transfer (p < 0.001).

Conclusions: The present study supports evidence that simple physicochemical properties related with lipophilicity, polarity, molecular size and ionization status exert significant impact on drugs and chemicals transport into human breast milk.     

Age dependent differences in stimulation and compensation of renal and biliary transport processes. Correlation to the physicochemical properties of the exerted substances

The relation between renal and biliary excretion of drugs was investigated in dependence on physicochemical factors, on age, and on repeated administration of hormones and xenobiotics for stimulation. Furthermore, the relation between molecular parameters of drugs and the degree of compensation of drug elimination after blockade of one excretion pathway (nephrectomy--NX, bile duct ligation--DL) was characterized. Experiments were performed on female 20-day and 55-day-old rats to demonstrate changes in the relationship between kidney and liver for drug elimination during ontogenesis. Finally it was tried to correlate the effect of a stimulation of elimination capacity of kidney and liver after repeated administration of hormones or xenobiotics and the physicochemical features of clearance substances tested. For estimation of physicochemical differences of the model substances a so called "rank coefficient" R (0-100) was used. It was calculated from molecular weight, lipophilicity, degree of ionization at pH 7.4, and protein binding rate. Compounds with low ranks (low values of molecular weight, lipophilicity, and protein binding, nearly completely ionic at pH 7.4) are eliminated first of all via urine. High ranks are typical of drugs preferentially eliminated into bile. Intermediate ranks (40-60) have been obtained for substances eliminated effectively both via kidney and liver. For these compounds only, a distinct compensation via the intact elimination route can be expected after blocking operations. Qualitative age differences could not be found. But there were differences concerning relation between acceleration of transport capacity of kidney and liver during postnatal maturation and physicochemical properties of the respective test substance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Substrate SARs in human P450s

Drug metabolism is now an integral part of the drug discovery process, and the cytochromes P450 (CYPs) are the most important family of enzymes involved in human drug metabolism. An increased understanding of the properties of the substrates for the major human CYPs is thus highly desirable. This article shows how key characteristics of CYP substrates, such as lipophilicity, molecular mass and hydrogen-bonding potential, govern selectivity towards individual CYPs. Importantly, the variation in binding affinities of 60 human CYP substrates can be explained by understanding the key physicochemical, structural and electronic characteristics that govern substrate binding to each isozyme.     

Kinetics of metabolism and degradation of mometasone furoate in rat biological fluids and tissues

Mometasone furoate (MF) is a potent glucocorticoid developed for the treatment of glucocorticoid-responsive inflammatory disorders. The in-vitro and ex-vivo kinetics of the degradation and metabolism of MF were studied in selected biological fluids of rat and subcellular fractions of different rat tissues. In-vitro, MF was found to degrade slowly into four products in serum and urine, and metabolized rapidly and extensively in rat liver, minimally in extrahepatic tissues, including intestine, stomach, lung and kidney. Further investigation found that the microsomal fraction was the major intracellular site of MF 6 beta-hydroxylation in rat liver. Using chemical inhibitors, CYP3A was found to be the major enzyme involved in the in-vitro MF 6 beta-hydroxylation in rat liver microsomes. Enzyme kinetic studies in rat liver microsomes showed that the overall metabolic process of MF followed biphasic Michaelis-Menten kinetics, while 6 beta-hydroxylation obeyed monophasic Michaelis-Menten kinetics. The kinetic parameters derived from the kinetic models along with the enzyme inhibition studies suggest that MF is mainly metabolized via 6 beta-hydroxylation mediated by CYP3A primarily, and also biotransformed via other pathway(s) catalysed by other enzymes in rat liver in-vitro.     

Influence of lipophilicity on the interactions of N-alkyl-4-phenyl-1,2,3,6-tetrahydropyridines and their positively charged N-alkyl-4-phenylpyridinium metabolites with cytochrome P450 2D6.

The relationship between lipophilicity and CYP2D6 affinity of cyclic tertiary (N-alkyl-4-phenyl-1,2,3,6-tetrahydropyridines) and quaternary (N-alkyl-4-phenylpyridinium) amines was examined. The 1,2,3,6-tetrahydropyridine scaffold was chosen due to its common occurrence in the structures of CYP2D6 ligands such as the Parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the dehydrated haloperidol metabolite N-[4-(4-fluorophenyl)-4-oxobutyl]-4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (HPTP). Likewise, the pyridinium framework is found in and 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium and N-methyl-4-phenylpyridinium (MPP(+)), the positively charged metabolites of MPTP and haloperidol. The lack of CYP2D6 inhibition by MPTP and its pyridinium metabolite MPP(+) was due to their hydrophilic nature since higher N-alkyl homologs revealed substantial increases in inhibitory potency against recombinant CYP2D6-mediated bufuralol-1'-hydroxylation. The reasonable correlation between lipophilicity and CYP2D6 inhibition by pyridiniums and 1,2,3,6-tetrahydropyridines was only limited to straight chain N-alkyl analogs, since certain N-alkylaryl analogs of lower lipophilicity were better CYP2D6 inhibitors. CYP2D6 substrate properties of straight chain N-alkyltetrahydropyridines were also governed by lipophilicity, and N-heptyl-4-phenyl-1,2,3,6-tetrahydropyridine was the optimal substrate (K(mapp) = 0.63 microM). Metabolism studies indicated that the N-heptyl analog underwent monohydroxylation on the aromatic ring and on the N-heptyl group suggesting that 1,2,3,6-tetrahydropyridines can bind in more than one conformation in the CYP2D6 active site. Increased lipophilicity of haloperidol metabolites did not correlate with inhibitory potency since the more lipophilic HPTP metabolite was less potent as an inhibitor than reduced-haloperidol and reduced-HPTP. Furthermore, HPTP and reduced-HPTP, of comparable lipophilicity to the N-heptyltetrahydropyridine analog were inactive as CYP2D6 substrates. This observation suggests that steric constraints rather than lipophilicity are responsible for the lack of CYP2D6 substrate properties of cyclic tertiary amines tethered to bulky N-substituents. This phenomenon appears to be a common theme among several cyclic tertiary amine-containing anti-depressants and should be taken into consideration when designing central nervous system agents devoid of CYP2D6 substrate properties.     

A literature review of enzyme kinetic parameters for CYP3A4-mediated metabolic reactions of 113 drugs in human liver microsomes: structure-kinetics relationship assessment

Cytochrome P450 (CYP) enzymes represent a superfamily of hemoproteins that are involved in the metabolism of a wide variety of endogenous and exogenous compounds. For a given CYP enzyme, kinetic properties of a substrate are usually related to substrate lipophilicity (log P or log D(7.4)). In this review, enzyme kinetic parameters (K(m), V(max), and V(max)/K(m)) of 215 CYP3A4-mediated metabolic reactions of 113 drugs in human liver microsomes were obtained from the literature, and lipophilicity values of the 113 drugs were calculated using the ACD/Labs 8.0 program. A low degree of K(m)- or (V(max)/K(m))-lipophilicity correlation, but no V(max)-lipophilicity correlation, is exhibited for the CYP3A4-mediated reactions. Overall, K(m) decreases, but V(max)/K(m) increases, with increasing substrate lipophilicity, and V(max) appears to be independent of substrate lipophilicity. In other words, a low K(m) generally confers a high V(max)/K(m) ratio for a substrate. The degree of lipophilicity-kinetics correlations is related to both reaction types (or reaction mechanisms) and regiochemical positions (or physicochemical properties) of the reaction groups of the substrates. Among the categorized CYP3A4-mediated reactions, the best lipophilicity-kinetics correlation is achieved for carbon hydroxylation, followed by N-dealkylation. No or little lipophilicity-kinetics correlations are seen for N, S-oxidation and other reactions. Within the hydroxylation group, aliphatic hydroxylation shows the best lipophilicity-kinetics correlation while hydroxylation on a carbon atom adjacent to an aromatic ring does not show any lipophilicity-kinetics correlation. The detailed structural and kinetic data sets of the human liver microsomal CYP3A4-mediated reactions represent a specialized database useful for researchers working in the area of structure-metabolism relationship modeling and analysis.     

Human cytochromes P450 associated with the phase 1 metabolism of drugs and other xenobiotics: a compilation of substrates and inhibitors of the CYP1, CYP2 and CYP3 families

This review represents a compilation of typical substrates and inhibitors for human cytochrome P450 (CYP) enzymes that are involved in drug metabolism, specifically those from the CYP1, CYP2 and CYP3 families. Relatively recent literature on substrates and inhibitors has been collected and the relevant K(m) and K(i) values, respectively, are tabulated. Furthermore, physicochemical properties in the form of lipophilicity (log P and log D(7.4) values) and acidity/basicity (pK(a) values) are also tabulated for a significant number of substrates, together with some information on inhibitors, although only key inhibitors have been selected as the main focus is on substrates. The collated information indicates that there are certain commonalities between substrates for the same enzyme, especially with respect to their positions of metabolism and likely interactions with the relevant enzyme active site regions. The compilation therefore assists in establishing substrate structure-activity relationships (SSARs) within human drug-metabolizing P450s.     

石斛酚与丁香酸的ADMET分子模拟预测

目的分子模拟预测石斛酚与丁香酸的吸收、分布、代谢、排泄和毒理性(ADMET),为进一步开发研究奠定基础。方法采用DS2.1中ADMET模块,从吸收性、水溶性、血脑屏障穿透性、与人细胞色素P450 2D6酶结合、肝毒性、与血浆蛋白结合6个方面进行测定。结果石斛酚的肝毒性比标准稍高,石斛酚与丁香酸的其他各方面的预测值都在正常范围内。结论石斛酚、丁香酸的ADMET测定结果符合药物研究开发的标准,可作为新药进一步研究。     

Lipophilicity in drug discovery

Importance of the field: The role of lipophilicity in determining the overall quality of candidate drug molecules is of paramount importance. Recent developments suggest that, as well as determining pre-clinical ADMET (absorption, distribution, metabolism, elimination and toxicology) properties, compounds of optimal lipophilicity might have increased chances of success in development. Areas covered in this review: The review covers aspects of methods of prediction of lipophilicity in frequent use and describes the most relevant literature analyses linking individual ADMET parameters and more composite measures of overall compound 'quality' with lipophilicity. What the reader will gain: The aim is to provide an overview of the relevant literature in an attempt to summarise where the optimum region of lipophilicity lies and to highlight which particular issues and risks might be expected when operating outside this region. Take home message: The review of the data shows that this optimal space is defined by a narrow range of logD between ～ 1 and 3. Some of the implications of this for medicinal chemistry optimisation are discussed.     

Chemoprevention of rat mammary carcinogenesis by Azadirachta indica leaf fractions: Modulation of hormone status,xenobiotic-metabolizing enzymes,oxidative stress,cell proliferation and apoptosis

We evaluated the chemopreventive potential of the ethyl acetate fraction (EAF) and methanolic fraction (MF) of Azadirachta indica (neem) leaf on 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary carcinogenesis. Estradiol and estrogen receptor status, xenobiotic-metabolizing enzyme activities, redox status, DNA and protein modifications, and the expression of cell proliferation, and apoptosis related proteins in the mammary gland and liver were used as biomarkers of chemoprevention. Administration of both EAF and MF at a dose of 10 mg/kg bw effectively suppressed tumour incidence. Chemoprevention by neem leaf fractions was associated with modulation of hormone and receptor status, xenobiotic-metabolising enzymes, and lipid and protein oxidation, with upregulation of antioxidants, inhibition of oxidative DNA damage, protein modification, and cell proliferation, and induction of apoptosis. However EAF rich in constituent phytochemicals was more effective than MF in modulating multiple molecular targets. These results provide evidence for the chemopreventive efficacy of neem leaf fractions in the rat mammary tumour model.     

Factors determining the relationship between renal and hepatic excretion of xenobiotics

Relation between kidney and liver in the excretion of drugs depends on the physicochemical properties of each substance tested. The calculations of this relationship are based on a so-called rank coefficient (0-100) calculated from molecular weight, lipophilicity, degree of dissociation under physiological conditions, and protein binding rate. The results of the correlation between one of these physicochemical values and drug elimination were stochastically. Experiments were performed with 9 test substances which were distinctly different concerning their physicochemical features. Substances with a rank coefficient less than 20 (low molecular weight, low lipophilicity, preferentially ionic at pH 7.4) are eliminated effectively via the kidney. Compounds having an intermediate rank coefficient (40-60) were quantitatively excreted into urine as well. For drugs with high ranks greater than 60 (high values of molecular weight, protein binding, and lipophilicity, almost exclusively nonionic), renal excretion can be neglected. Quite inverse relations between ranks and hepatic excretion have been found: low ranks indicate an ineffective secretion of the respective drug into bile. With increasing ranks (40-60), biliary excretion increases and reaches a maximum (approximately 40% of supply). This maximum is caused by limited hepatic blood flow and by the capacity of hepatic uptake carriers. Blockade of one elimination pathway (bilateral nephrectomy or bile duct ligation) is followed by a sufficient compensation of drug excretion via the alternative elimination route only, if the test substance belongs to the intermediate group (ranks between 40 and 60). For substances with high or low ranks a compensation of drug excretion can be excluded.     

Pharmaceutical profiling in drug discovery

Drug discovery research organizations are building capability for measuring an ensemble of crucial 'drug-like' properties. These structure-property relationship (SPR) data complement current SAR information. This pharmaceutical profiling strategy enables research teams to better plan and interpret discovery experiments, be alerted to potential 'show stoppers', improve property liabilities, and select the best candidates for advancement. High throughput property assays for physicochemical properties--solubility, permeability, lipophilicity, stability, and pK(a)--in vitro ADME--metabolism, transporters, protein binding and CYP inhibition--and in vivo PK/exposure provide a wealth of data for teams to make informed decisions.