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									                                                                      Molecular Similarity as a guide to Safety Pharmacology
                                                                                                  Fiona T. Mc Cahey1*, Philip M. Marsden1, Andreas Bender1, Jos W. M. Tissen2, Werner Klaffke2, Robert C. Glen1
                                                                                                                                1   Unilever Centre for Molecular Informatics, Chemistry Department, University of Cambridge, Cambridge CB2 1EW, United Kingdom
                                                                                                                                           2 Unilever Research Vlaardingen Laboratory, Olivier van Noortlaan 120, NL-3133AT Vlaardingen, The Netherlands

                                                                                                                                                                        * Corresponding author email address

Introduction                                                                                                                 Results
The prediction of both the main therapeutic activity and side-effects (Safety
Pharmacology) of both existing and new drugs is of major importance to the                                                   Using 5-fold cross-validation, the average correct hit rate (number of compounds correctly predicted to be active and inactive)
pharmaceutical industry. A recent estimate suggests that it takes 10-15 years to                                             using this method is 90.37% over 154 activity classes (Table 1). Ranking of classes shows that 76% of compounds were correctly
produce a new drug at an average cost of U.S.$800 million (1). Much of this cost                                             predicted to be in the top ranked class and 90% were in the top 3 (Table 2). Therefore it appears that SARs created by MOLPRINT
could be reduced if there was a reliable and inexpensive way in which to determine                                           2D can differentiate between drugs that act at different target receptors. Centroid-linkage hierarchical clustering indicates that data
the in vivo effects of a compound. We present our work to create an in silico screen,                                        fall into clusters corresponding to receptors of similar type (e.g. aminergic GPCR receptors) (Figure 3) . ALL of the main                                                                                                                                                                       1. 5HT reuptake inhibitor

which is analogous to an in vitro receptor screening assay, using fragment-based                                             therapeutic effects of the top 10 selling drugs were predicted correctly using the model. Some of the main side-effects can also be                                                                                                                                                              2. 5HT1A agonist

molecular similarity methods. We have used circular fingerprints to analyse                                                  explained using the model (Table 3).                                                                                                                                                                                                                                                             3. 5HT1A antagonist
approximately 50,000 biologically active compounds. The top 10 selling drugs in the                                                                                                                                                                                                                                                                                                                                           4. 5HT2A antagonist
U.S. in 2004 (2) have been tested in the model, and their predicted therapeutic and                                                                                                                                                                                                                                                                                                                                           5. Adrenergic (alpha1) blocker
                                                                                                                                                                                                                                        Rank position                                 % correct
side-effect profiles have been compared to their known clinical effects.                                                                                                                                                                                                                                                                                                                                                      6. Dopamine D4 antagonist
                                                                                                                                                                                                                                                    1                                    75.7                                                                                                                                 7. Dopamine D2 antagonist
                                                                                                                                    % predicted             correct                incorrect
                                                                                                                                                                                                                                                Top 2                                    86.1
                                                                                                                                                                                                                                                                                                                                             Figure 3: Centroid-linkage hierarchical clustering model, created in R (6). Small section enlarged to show
Method                                                                                                                              active                  84.36                 15.64
                                                                                                                                                                                                                                                Top 3                                    89.7
                                                                                                                                                                                                                                                                                                                                             seven individual classes in a cluster.
Database Used
Approximately 50,000 biologically active compounds in 154 activity classes from the MDL Drug Data Report
                                                                                                                                    inactive                96.38                 3.62                                                          Top 5                                    92.9
database (MDDR) (3) were chosen for characterisation.
MOLPRINT 2D                                                                                                                         Average                 90.37                 9.63                                                         Top 10                                    96.4                                                Molecular similarity does appear to be useful both in identifying the principal mode of
The MOLPRINT 2D method uses atom environment descriptors (Figure 1), information-based feature
selection and a naïve Bayesian classifier to classify compounds in each activity class (4).                                                                                                                                                                                                                                                  action of a drug molecule and in identifying some side effects. The correct hit rate of
Descriptor Generation: Atom Environments,                                                                                     Table 1: Results of 5-fold cross-validation                                                        Table 2: Results of ranking all activity classes for each molecule                                          90.37% over 154 classes (as shown by cross-validation) using MOLPRINT2D can be
(Circular Fingerprints) for every atom in the molecule are                                                                                                                                                                                                                                                                                   compared to that of the PASS (Prediction of Activity Spectra for Substances) program,
 calculated using bond distances from 0 up to 2 bonds.
SYBYL® ( atom types are used to derive the environments as
                                                                                                                                                                                                                                                                                                                                             which has a reported hit rate of 85% over 1000 types of biological activity (8). To improve
they partially capture physicochemical properties                                                                                                                                                                                                                                                                                            this hit rate further, the occurrence of false positives (compounds that have been
(hybridisation, geometry and electronic structure).                                                                                                                                                                                                                                                                                          predicted as active at a receptor, but are not reported as such in the MDDR database)
                                                           Figure 1. Atom Environment Descriptor generation                                                                                                                                                                                                                                  could be due to the presence of many highly correlated receptor classes for which there
Calculations Performed
                                                                                                                        Rank        Structure               Proprietary Name    Clinical effect                          Main side-effects                       Predicted Target from       Clinical effects Explained?                     may only be one activity reported in the database (of course, this dataset is not
                                                                                                                                                            (generic name)      and Target                                                                       Molprint analysis
                                                                                                                                                                                                                                                                                                                                             comprehensive and contains activities, not inactivities). All of the therapeutic effects of
1.MOLPRINT2D was used to create qualitative Structure Activity relationships (SARs) for each activity class.
                                                                                                                        1                                   LIPITOR             Treats hypercholesterolemia by           Reversible myositis, myalgia,           HMG CoA reductase (beta)    Therapeutic effect – yes. Side effects          the top 10 selling drugs were predicted correctly using the models. Some side-effects
                                                                                                                                                                                competitively inhibiting HMG CoA         myopathy                                inhibitor                   are not well understood
                                                                                                                                                            (Atorvastatin)                                                                                                                                                                   can also be explained, in particular those side-effects that can be characterised by
2.Euclidean distances and Pearson’s correlation coefficients between all (154) activity classes were                                                                            reductase

calculated.                                                                                                                                                                                                                                                                                                                                  predicted activity due to specific receptors (e.g. blood pressure lowering from agonists at
                                                                                                                        2                                   ZOCOR               Treats hypercholesterolemia by           Reversible myositis, myalgia,           HMG CoA reductase (beta)    Therapeutic effect – yes. Side effects          the 5HT2A receptor). Side-effects such as “headache” which have many physiological
                                                                                                                                                                                competitively inhibiting HMG CoA         myopathy                                inhibitor                   are not well understood
3.Centroid-linkage hierarchical clustering was carried out on the data using R (6) (Figure 3).                                                              (Simvastatin)
                                                                                                                                                                                reductase                                                                                                                                                    and psychological reasons for occurrence may not be specific to individual receptors and
                                                                                                                                                                                                                                                                                                                                             are not particularly easy to explain by this approach. However, further literature searches
4.Pearson’s correlation coefficients between ALL (452) activity classes in the MDDR were calculated to create
an in vitro-in vivo (target-effect) matrix. This can be used to find if the data suggests that certain targets (e.g.    3                                   PREVACID            Ulcer healing by inhibiting “proton      GI disturbances (nausea, vomiting,      H+/K+ -ATPase Inhibitor     Therapeutic effect- yes. Side-effects           could indeed identify measured effects similar to those predicted. Using hierarchical
                                                                                                                                                                                pump”                                    abdominal pain, flatulence)                                         caused by many factors
HMG-CoA reductase inhibitor) can be linked to certain effects (e.g. Hypolipidemic).                                                                         (Lansoprazole)                                                                                                                                                                   clustering (based on the occurrence of the fragments present in the compounds making
                                                                                                                                                                                                                                                                                                                                             up each of the classes) many clusters appear to contain very similar receptor types. This
5.A comparison of all activity classes was performed by combining the SARs from each individual activity
                                                                                                                        4                                   NEXIUM              Ulcer healing by inhibiting “proton      GI disturbances (nausea, vomiting,      H+/K+ -ATPase Inhibitor     Therapeutic effect- yes. Side-effects           is consistent with similar binding and activation characteristics being present in these
class as determined by MOLPRINT 2D. A 5-fold cross-validation and ranking of all classes against individual                                                 (Esomoprazole)      pump”                                    abdominal pain, flatulence).                                        caused by many factors
compounds was carried out. The rationale behind assigning a molecule as belonging to an active or inactive                                                                                                               Dermatitis                                                                                                          molecules (pharmacophores).
set in the cross-validation can be seen in Figure 2.
                                                                                                                        5           PROTEIN                 PROCRIT                                                                                              CANNOT be predicted by
                                                                                                                                                                                                                                                                                                                                             Future Work
6. A list of the top 10 selling drugs in the U.S. in 2004 was created. Structures were collected from various                                               (Epoetin alfa)                                                                                       model
sources and information on therapeutic effects and side-effects was collected from the British National                                                                                                                                                                                                                                      A more specific and comprehensive database containing activities at each receptor
Formulary (BNF) (7).                                                                                                    6                                   ZOLOFT              Antidepressant -SSRI                     Nausea, vomiting, GI bleeding           Glutamate receptor          Therapeutic effect-yes. Target has high         (positive and negative) would be beneficial in model building and validation. Access to
                                                                                                                                                                                                                         disorders                               antagonist                  correlation to Antidepressant and
                                                                                                                                                                                                                                                                                             Antipsychotic effects
                                                                                                                                                                                                                                                                                                                                             this type of data will be pursued. Also, investigation of additional/alternative descriptors
7. The top 10 selling drugs were tested in the model to find if their therapeutic and side-effects were correctly
                                                                                                                                                                                                                                                                                                                                             (such as clogP or MOLPRINT3D) will be tested in order to improve the current models.
                                                                                                                        7                                   PLAVIX              Prevention of athersclerosclerotic       Dyspepsia, abdominal pain,              Somatostatin Antagonist,    Therapeutic effect-yes. Targets have
                                                                                                                                                            (clopidogrel)       events                                   diarrhoea, GI bleeding, intercranial    Bradykinin BK2 antagonist   high correlation to Anticoagulant and           Additional comparisons with other methods and data will be informative in determining
                                                                                                                                                                                                                         bleeding                                                            antiaggregatory effects. This may also
                                                                                    S = SCORE                                                                                                                                                                                                be the cause of bleeding side effects
                                                                                                                                                                                                                                                                                                                                             the usefulness of this approach. Testing of compounds such as the top 200 selling
                                                                                                                                                                                                                                                                                                                                             drugs, new-to-the-market drugs, compounds that failed in clinical trials and traditional
                                                                                    NA = total number in active set
                                                                                                                                                                                                                                                                                                                                             Chinese medicines will be pursued to ascertain if the model is reliable and makes
                                                                                    NI = total number in inactive set                                                                                                                                                                                                                        useful testable predictions.
                                                                                                                        8                                   ADVAIR DISKUS       Nasal allergy                            Dryness, irritation and ulceration of   Corticosteroid              Therapeutic effect-yes. Target has high
                          NI                                                        NAO = number of actives below                                           (fluticasone                                                 nose and throat. Raised Intra-                                      correlation with Anti-inflammatory effect
                                                           NA                       S                                                                       proprionate)                                                 ocular pressure and glaucoma                                        and Ophthalmic effect. The latter may
                                                                                                                                                                                                                                                                                             be the reason for ocular side-effects
                                                                                                                                                                                                                                                                                                                                             Development of a comprehensive in-vitro and in-vivo (target-effect) ontology for both
                                        NAO NIO                                     NIO = number of inactives above
                                                                                                                                                                                                                                                                                                                                             therapeutic effects and side-effects will allow better relationships to be developed
         INACTIVES                                        ACTIVES
                                                                                    S                                                                                                                                                                                                                                                        between receptor activities and medicinal effects.
                                                                                                                        8                                   ADVAIR DISKUS       Bronchodilator- selective beta 2         Fine tremor (particularly in hands),    Adrenergic (beta) agonist   Therapeutic effect-yes. Side-effects-
                      MOLPRINT Score (S)                                            PA = NAO/NA                                                             (salmeterol)        agonist                                  headache, nervous tension                                           Target has high correlation with
                                                                                                                                                                                                                                                                                             spasmolytic effect (tremor) and
                                                                                    PI = NIO/NI                                                                                                                                                                                              anxiolytic (nervous tension)                    (1) IFPMA, 15 Ch. Louis-Dunant, PO Box 195, 1211 Geneva 20, Switzerland
When PA / (PA + PI) > C, molecule is active
                                                                                    C = cutoff, a user defined                                                                                                                                                                                                                               (2) NDCHealth, NDC Plaza, Atlanta, GA 30329-2010, USA
      PA / (PA + PI) < C, molecule is inactive                                                                          9                                   ZYPREXA             Atypical antipsychotic                   many                                    5HT3 agonist, D1            Therapeutic effect-yes. Atypical
                                                                                    number which biases model                                               (olanzapine)                                                                                         antagonist, 5HT2A           antipsychotic drugs act at many                 (3) MDL Information Systems, Inc., 14600 Catalina St., San Leandro, CA 94577-6608
                                                                                                                                                                                                                                                                 antagonist, D2 antagonist   receptors in the CNS
                                                                                    towards assigning a compound                                                                                                                                                                                                                             (4) Bender, A.; Mussa, H. Y.; Glen, R. C.; Reiling, S.; J. Chem. Inf. Comput. Sci. 2004; 44(1); 170-178
                                                                                    as active or inactive. C was                                                                                                                                                                                                                             (5) SYBYL 7.0, Tripos Inc., 1699 South Hanley Rd., St. Louis, Missouri, 63144, USA
                                                                                    optimised to reduce numbers of
                                                                                    false   positives  and   false      10                                  CELEBREX            NSAID to treat rheumatic disease and     GI discomfort, nausea, bleeding,        Neurotensin receptor        Therapeutic effect-yes. Target has high         (6) Development Core Team (2004). R: A language and environment for statistical computing. R Foundation for
                                                                                                                                                            (celecoxib)         gout. Also treats familial adenomatous   ulceration                              antagonist                  correlation with anti-arthritic effect, anti-       Statistical Computing, Vienna, Austria
                                                                                    negatives                                                                                   polyposis (FAP)                                                                                              inflammatory effect. Side-effect: target
                                                                                                                                                                                                                                                                                             has high correlation with agent for             (7) Joint Formulary Committee. British National Formulary. 49 ed. London: British Medical Association and Royal
                                                                                                                                                                                                                                                                                             inflammatory bowel disease effect                   Pharmaceutical Society of Great Britain; 2005
Figure 2: Assigning membership of a molecule, based on its MOLPRINT score to the active or inactive set
                                                                                                                                                                                                                                                                                                                                             (8) Poroikov, VV; Filimonov, D.A; Borodina, Y.V.; Lagunin, A.A.; Kos, A. J. Chem. Inf. Comput. Sci.2000,
                                                                                                                        Table3: Results of testing the top 10 selling drugs in the U.S. in 2004 in the model.                                                                                                                                Acknowledgments
                                                                                                                                                                                                                                                                                                                                             We would like to thank Unilever for funding

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