REVIEW OF METHODS FOR ASSESSING THE APPLICABILTY DOMAINS OF SARS AND QSARS

PAPER 4: SAR Applicability Domain

Authors: Dr Joanna Jaworska (Procter & Gamble, Strombeek Bever, Belgium) E-mail: jaworska.j@pg.com Dr Nina Nikolova (Bulgarian Academy of Sciences, Sofia, Bulgaria) E-mail: nina@acad.bg

Sponsor: The European Commission - Joint Research Centre Institute for Health & Consumer Protection - ECVAM 21020 Ispra (VA) Italy Contact: Dr Andrew Worth E-mail: andrew.worth@jrc.it http://ecb.jrc.it/QSAR JRC Contract ECVA-CCR.496575-Z

VERSION OF 27 SEPTEMBER 2004

SAR applicability domain

Nina Nikolova and Joanna Jaworska Introduction Structure Activity Relationships (SAR) are relations between the molecular structure and biological or physicochemical activity of chemicals [1]. Some authors regard Quantitative SARs as a special case of SARs (when relationships become quantified), while other exploit notions of chemical similarity to predict the activity of chemicals. The latest is also known as read-across approach, meaning the unknown property of a compound is decided to be the same as the known property of another compound if the two compounds are sufficiently similar. This is a source for an ambiguity in the SAR science ( see definitions section at the end of the document), since the similarity is a subjective term, and there is a great diversity in type and extent of similarities [2,3]. Similarity can be assessed directly by structural similarity or indirectly by first converting a structure to its numerical representation (i.e. molecular descriptors, field descriptors) and then applying one of similarity measures. If a transformation of the structure to a numerical representation occurs the method to assess similarity becomes quantitative. The reliability of the measure depends on the relationship between numerical representation of chemicals (i.e descriptors) and activity and this relationship should be known (or derived). Thus such a SAR is a special case of QSAR we will call it qSAR. Applicability domain of such a qSAR reduces to applicability of a QSAR. In qualitative, classic SAR the similarity is based on in structural similarity. The structural similarity has been heavily exploited, however current research shows that it does not always imply similarity in activity (Martin et al. 2002). Further structural similarity does not always imply similarity in descriptors (Kubinyi, 2001). Therefore, structural similarity should be used with care and has to be justified in every specific case. Notion of similarity on regard to specific activity accompanied by mechanistic 1

understanding is a useful framework to study similarity in activity by similarity in structure. Similarity in qSARs Although the similarity is a convenient idea for humans, the attempts to define it rigorously has led to its controversial status in philosophy [4] and to a set of diverse implementations in toxicology. Some philosophers believe that it is ill defined to say A is similar to B and it is only meaningful to say A is similar to B with respect to C [5]. This has important implications for toxicology a chemical A cannot be similar to a chemical B in absolute terms but only with respect to some measurable key feature. Various approaches of measuring chemical similarity have been recently reviewed in [2, 3]. A chemical compound is usually represented by fingerprints, descriptors (more than 3000 available), electron density or various fields [2]. All these representations involve the loss of information and the modeler should ensure the lost information is not important. This could be done by expert by the use of proper statistical techniques having in mind that no numerical representation is unique; a numerical representation includes only a part of all the information about the compound; What is actually measured is the distance between specific numerical representations of chemical compounds, not the similarity in activity directly. A distance measure reflects closeness in descriptor space only if the data holds specific assumptions (i.e. a distance could give results which are not always expected intuitively; for example Euclidean distance gives good results with normally distributed data with uncorrelated descriptors) . Once similarity by descriptors is estimated, it is used to make decision on similarity in activity, based on the assumptions mentioned above and sometimes known as neighborhood principle, i.e. molecules in the same local region (neighbourhood) of a descriptor space tend to have similar values of a desired property. The principle is rarely questioned, but contradictory evidence exists: both supporting and rejecting. The analysis of the neighborhood principle [2] revealed that proximity with 2

respect to descriptors does not necessary mean proximity with respect to the activity. This is only true if a linear relationship holds between descriptors and activity. The linear relationship is only a special case, given the complexity of biochemical interactions and its application should be justified in every specific case. Similarity in SARs The rationale behind SAR is that the structure of the chemical implicitly determines its physical and biological properties and reactivity, which in interaction with a biological system, determine its biological / toxicological properties [6]. Therefore, the science of SAR is in relating the structure to activity, i.e. identifying the key aspects of structure, pertaining to the molecular event(s) in the mechanism of action for the chemical or biological actions of interest. The direct structural similarity is a very exploited one, however, it is often unsuccessful (does not always imply similarity in activity) [7,8] mainly because key aspects of the structure related to activity are not known. Here is a classic example from such a case. A SAR case study (Skin sensitization) As a first step to testing SAR, a list of classes of chemicals that share structural features having effects on sensitization is compiled [1, Figure 1]. The list is distilled from an extensive literature search and represents expert opinion. Figure 1. A list of classes of chemicals that share structural features having effects on skin sensitization.

Verification

A recently published data set [9] of skin sensitization data offers the possibility to evaluate the significance of structural features, compiled 3 years ago. The results are listed below: Amines. Benzocaine is a nonsensitizers, while p-Phenylenediamine is a strong and ethylenediamine is a moderate sensitizer; Aldehydes. Formaldehyde and glutaraldehyde are a strong sensitizers; cinnamic aldehyde is a moderate sensitizer. However, within the set of 19 aldehydes available in the data set, two are strong (formaldehyde and glutaraldehyde), 7 are moderate , 7 are weak and two are nonsenstizers. Phenols. Isoeugenol is a moderate sensitizer (EC3=3.5); eugenol is a weak sensitizer; 3methyl catechol is a strong sensitizer. A possible explanation can be found in [10]. Chlorides. 1-Chloro-2,4-dinitrobenzene is an extreme sensitizer Thioles. 2-Mercaptobenzothiazole is a weak sensitizer The above results support the evidence that structural similarity, even reviewed by experts, may lead to suprizes and is not equivalent to similarity in activity. Discussion SARs are based on the notion of structural similarity: Similar compounds have similar activity. The principle is assumed, but in the reality it is not always true. In our view the applicability domain of a SAR model estimation is equivalent to finding the set/classes of compounds where the similarity assumption is valid for a specific activity. Practical experience (RIVM 2001 workshop and ECETOC 2003 report) is that current SARs softwares should be used only for positive indication. For example, DEREK does not respect activating or detoxifying mechanisms in a balanced way and it is geared towards finding active substances based on parent structure. In addition DEREK does not discriminate between non-toxic compounds and compounds for which there is no information on toxicity available.

Definitions 1. Structure activity relationship (SAR). The analysis of the dependence of the biological effects of a chemical upon its molecular structure produces a structure activity relationship. Molecular structure and biological activity are correlated by observing the results of systematic structural modification on defined biological endpoints.[11] 2. Structure-activity relationship is the relationship between chemical structure and pharmacological activity for a series of compounds.[12] 3. PTCL Safety Glossary: Structure-Activity Relationship [13].The Structureactivity relationship (SAR) is a means by which the effect of a drug or toxic chemical on an animal, plant or the environment can be related to its molecular structure. This type of relationship may be assessed by considering a series of molecules and making gradual changes to them, noting the effect upon their biological activity of each change. Alternatively, it may be possible to assess a large body of toxicity data using intelligent tools such as neural networks to try to establish a relationship. Ideally, such relationships can be formulated as Quantitative Structure-activity relationship (QSARs), in which some degree of predictive capability is present. 4. Structure Activity Relationship SAR: The relationship between chemical structure and pharmacological activity for a series of compounds [IUPAC Medicinal Chemistry] Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Other factors contributing to structure- activity relationship include chemical reactivity, electronic effects, resonance, and inductive effects [14] 5. Structure-property correlations refers to all statistical mathematical methods used to correlate any structural property to any other property (intrinsic, chemical or biological), using statistical regression and pattern recognition [15].

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14. http://www.genomicglossaries.com/content/drug_discovery_gloss.asp 15. http://www.chem.qmul.ac.uk/iupac/medchem/ix.html#s5