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Probing the links between in vitro potency, ADMET and physicochemical parameters

Nature Reviews Drug Discovery volume 10, pages 197–208 (2011)Cite this article

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Key Points

  • Basic physicochemical properties of molecules such as molecular mass and logP (lipophilicity) are of considerable importance in defining their overall biological profile. In this article, we discuss the links between molecular mass, logP and biological characteristics such as potency, selectivity–promiscuity and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties.

  • This study uses data sourced from the publicly available ChEMBL database. Such databases are becoming an increasingly valuable source of information in pharmaceutical research. The key advantage of such data is that analyses can be done in an open manner, and thus can be critically assessed by others. This contrasts to many informatics analyses reported on proprietary datasets of large pharmaceutical companies.

  • Receptor potency and desirable ADMET parameters generally show a diametrically opposed relationship to the key molecular properties, namely molecular mass and logP. In addition, it is shown here that the promiscuity of molecules on average increases with increasing molecular mass and logP. This suggests the level of potency sought in a candidate molecule must be carefully balanced with physical properties, ADMET characteristics and promiscuity.

  • The oral drug set compiled here has a median pXC50 of 7.7 (∼50 nM) and shows what might be considered a less than 'clean' selectivity profile. Furthermore, the correlation between the mean therapeutically relevant pXC50 of a compound and its mean therapeutic dose is weak (r2 = 0.26), suggesting a focus on high levels of potency in drug discovery projects may not always be necessary.

  • A move towards a drug discovery process with less emphasis on data-driven decisions based on often qualitative high-throughput model systems seems to be desirable. A more precise assessment of the therapeutic potential of the molecules through a more complete consideration of the necessary biological parameters should lead to greater success of research and development efforts.

Abstract

A common underlying assumption in current drug discovery strategies is that compounds with higher in vitro potency at their target(s) have greater potential to translate into successful, low-dose therapeutics. This has led to the development of screening cascades with in vitro potency embedded as an early filter. However, this approach is beginning to be questioned, given the bias in physicochemical properties that it can introduce early in lead generation and optimization, which is due to the often diametrically opposed relationship between physicochemical parameters associated with high in vitro potency and those associated with desirable absorption, distribution, metabolism, excretion and toxicity (ADMET) characteristics. Here, we describe analyses that probe these issues further using the ChEMBL database, which includes more than 500,000 drug discovery and marketed oral drug compounds. Key findings include: first, that oral drugs seldom possess nanomolar potency (50 nM on average); second, that many oral drugs have considerable off-target activity; and third, that in vitro potency does not correlate strongly with the therapeutic dose. These findings suggest that the perceived benefit of high in vitro potency may be negated by poorer ADMET properties.

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Figure 1: Relationship between ADMET parameters and physicochemical properties.
Figure 2: Relationship between in vitro potency and physicochemical properties.
Figure 3: Relationship between promiscuity and physicochemical properties.
Figure 4: Relationship between promiscuity and ionization state.
Figure 5: Relationship between in vitro potency and dose for oral drugs.
Figure 6: Promiscuity of oral drugs.

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Acknowledgements

M.P.G., A.H. and D.M. are grateful to many former colleagues at GlaxoSmithKline for insightful discussion on this topic. M.P.G. gratefully acknowledges support from the Faculty of Science at Kasetsart University as well as additional assistance from S. Hannongbua and S. Ruchirawat. The authors thank J. Proudfoot (Boehringer Ingelheim Pharmaceuticals) for kindly providing a copy of his oral-drug dataset. ChEMBL data collection, database maintenance and support are funded through a Wellcome Trust award.

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Author notes

  1. Dino Montanari

    Present address: Present address: Aptuit Srl, Medicines Research Centre, Via A. Fleming, 4, 37135, Verona, Italy.,

  2. paul.gleeson@ku.ac.th

Authors and Affiliations

  1. The Department of Chemistry, Faculty of Science, Kasetsart University, 50 Phaholyothin Road, Chatuchak, 10900, Bangkok, Thailand

    M. Paul Gleeson

  2. EMBL-EBI European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, Cambridgeshire, UK

    Anne Hersey & John Overington

  3. The Neurosciences CEDD, GlaxoSmithKline Medicines Research Centre, Via A. Fleming, 2, 37135, Verona, Italy

    Dino Montanari

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Supplementary information

Supplementary information Figure S1

The relationship between four different ADMET parameters and either molecular mass or logP. (PDF 294 kb)

Supplementary information Figure S2

The relationship between 4 different ADMET parameters and the ADMET score. (PDF 318 kb)

Supplementary information Figure S3

The relationship between the in vitro potency, molecular mass and xlogP for five different chemotypes, each acting at a single target (PDF 317 kb)

Supplementary information (XLS 25582 kb)

Supplementary information (XLS 423 kb)

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FURTHER INFORMATION

Cerep Bioprint database

ChEMBL database

Drugbank

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Pubmed

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The Journal of Pharmacology and Experimental Therapeutics

Glossary

Potency

A measure of drug activity expressed in terms of the amount of drug required to produce an effect of given intensity. Common measures of potency include the half-maximal inhibitory concentration (IC50) values for receptor antagonists and half-maximal effective concentration (EC50) values for receptor agonists.

QT interval prolongation

The QT interval is a measure of the total time of ventricular depolarization and repolarization. Unexpected reports of sudden cardiac death associated with prolongation of the QT interval have caused several drugs to be withdrawn from the market in recent years. Blockade of the HERG channel has been linked to this effect.

XC50 value

The concentration of a substance that results in a 50% of the maximal effect of the substance on a biochemical function (for example, inhibition/antagonism as given by the IC50 value or agonism/stimulation as given by the EC50 value).

Molecular mass

Frequently also called the molecular weight, this refers to the mass of one molecule of that substance. Its unit is the Dalton (Da), which equals 1/12 the mass of one atom of carbon-12.

LogP

The logarithm of the octanol–water partition coefficient, which is a measure of a molecule's preference for aqueous or lipophilic environments, and can be used to rationalize the ability of molecules to cross biological membranes. It is defined as the ratio of un-ionized drug distributed between the octanol and water phases at equilibrium. Larger values imply greater lipophilicity.

Rule of five

Lipinskis 'rule of five' identifies several key physicochemical properties that are desirable in small molecules that are intended to be orally administered drugs; specifically, molecular mass <500 Da; number of hydrogen-bond donors <5; number of hydrogen-bond acceptors <10; calculated octanol–water partition coefficient <5.

Oral-drug space

A generic term to describe the area of chemical space in which oral drugs have a high probability of being found. It can in principle be defined using any number of physicochemical or theoretical descriptors.

AlogP

A theoretical prediction of LogP determined by a fragment-based method.

Ligand efficiency

A simple metric that provides a measure of the binding affinity per unit mass of a molecule.

pXC50 value

The negative logarithm of the XC50 value. Thus, pXC50 = 9 for a compound with XC50 = 1 × 10−9 M (nanomolar potency).

Druggability

The druggability of a target is a measure of the probability that a successful molecular therapy can be developed for that target.

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Gleeson, M., Hersey, A., Montanari, D. et al. Probing the links between in vitro potency, ADMET and physicochemical parameters. Nat Rev Drug Discov 10, 197–208 (2011). https://doi.org/10.1038/nrd3367

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