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					                                                                                   FBSS : Using Molecular Fields as a Novel Alignment Method for 3D QSAR

                                                                          Valerie                                     Gillet1,                                     Nick                            Jewell 1,   Graham J.                                 Sexton 2,                     David B.             Turner 1                             and Peter                                 Willett1
University of                                                                                                                                                                                                                                                                                                                                                                                                                                                     University of
 Sheffield                                                                                                                                                                                                                                                                                                                                                                                                                                                         Sheffield
                                                                                                  GA Parameter                                                     GA Value
The Field-Based Similarity Searcher (hereafter known as FBSS) has been                            GA Operations                                                    10000                                                                                                                                    Melatonin Receptor Antagonists :
developed by researchers at the University of Sheffield. FBSS can align                           GA Population Size                                               125
series of molecules by optimising the molecular field overlap between the                         GA Selection Pressure                                            1.10
                                                                                                                                                                                                                                                                                                            A CoMFA Model Developed Using
compounds using a Genetic Algorithm (GA). Previous work has focussed                              Flexibility                                                      RIGID and FIX-FLEX                                                                                                                       FBSS Alignments
on the alignment of structures to assess three-dimensional molecular                                                                                               (see text)
                                                                                                  Initial Population                                               Randomly Generated                                                                                                                       Melatonin is the principal hormone of the vertebrate pineal gland in
similarity in database searching, with results in this matter being published
                                                                                                                                                                   and Diverse                                                                                                                              humans. The production cycle within the body correlates with
elsewhere. [1]
                                                                                                                                                                   (using Hamming Distance)                                                                                                                 conditions of light and darkness surrounding the body, with high
                                                                                                                                                                                                                                                                                                            concentrations being produced during periods of darkness, for example
Comparative Molecular Field Analysis (hereafter, CoMFA) [2] has
                                                                                                                                      Figure 2: Basic FBSS Parameters                                                                                                                                       at night. Melatonin inhibitors are finding new applications in the field
become one of the most popular methods to develop three-dimensional
                                                                                                                                                                                                                                                                                                            of anti-cancer treatments, where the compounds appear to act as anti-                           Figure 8: Steric and Electrostatic (coefficient*stdev) plots
quantitative structure-activity relationships (3D-QSAR). The basic
CoMFA method is shown in Figure 1 below, although it is relatively                    Testing the Relationship between Q2                                                                                                     Figure 4: Electrostatic and Steric (coefficient*stdev) contour
                                                                                                                                                                                                                                                                                                            tumour agents.                                                                                                   for the FBSS Alignment
common for researchers to alter key aspects of the CoMFA process, such                                                                                                                                                                                                                                                                                                                                             (Contour levels of 10.0 and 90.0 are used)
as the calculation of novel molecular fields or the adoption of new
                                                                                      and Molecular Similarity                                                                                                                     plots for the CBG Steroids after FBSS Alignment                          A previous 3D-QSAR experiment conducted by Sicsic et al. [5]
                                                                                                                                                                                                                                (Hydrogen Suppressed). Default contour values are used.                     utilised a training set of 48 compounds, all of which show some                      The manual alignment and CoMFA model presented here are the results
statistical procedures.
                                                                                      The main assumption underlying this work is that by                                                                                                                                                                   antagonist potency towards the melatonin receptor. The training set                  of testing many different alignment rules. This manually-derived
                                                                                      aligning compounds based on their molecular similarity to                                                                                                                                                             was built from a variety of rigid core structures which are summarised
   1. Alignment of structures (either template-, functional group- or                                                                                                                                                                                                                                                                                                                            ‘optimum’ model performs as robustly (as indicated by Q2) and more
                                                                                      a target compound, and then by using that alignment to                                                                                                                                                                in Table 3.
   field-based).                                                                                                                                                                                                                                                                                                                                                                                 predictively (as indicated by pr-R2) than the FBSS-derived model. But
                                                                                      generate a CoMFA model, better Q2 values will be                                                                                                                                                                       Chemical Family of   Number of Training       Compound         Notes (see below)    the major advantage of using the FBSS procedure is that it proceeds
                                                                                      obtained.                                                                                                                                                                                                               Core Structure       Set Compounds in    Reference Numbers
   2. Placement of structures within a molecular lattice.                                                                                                                                                                                                                                                                                Class              from [5]                             automatically and produces a very similar model (in terms of both
                                                                                      By running FBSS with various GA settings, we are able to                                                                                                                                                                 Indole-based                9                   1-9                 *             statistics and suggesting direction for further drug design).
                                                                                                                                                                                                                                                                                                             Naphthalene-based            23                  10-32                *
   3. Sampling of electrostatic and steric molecular fields at grid                   generate a series of molecular alignments that vary in their                                                                                                                                                               Tricyclic                 2                  33,34                +
   intersections within the lattice.                                                  precision. As part of the software’s output, a value for the                                                                                                                                                            Tetraline-based
                                                                                      mean similarity between compounds and the target
   4. Statistical analysis (usually Partial Least Squares) producing a                structure is obtained. This can be compared to the Q2 of the                                                                                                                                                                  Notes: Compounds with (*) contain a highly-flexible
   descriptive model from the molecular field data.                                   CoMFA model generated from the overlay. For the                                                                                                                                                                               ethylamido side chain on the aryl-group
                                                                                      benchmark steroid data set, Figure 3 shows a graph of the                                                                                                                                                                     Compounds with (+) contain the ethylamido group                               The FBSS program can align any set of structures for which there is
   5. Analysis of model, including the removal of outliers and                        relationship between these values; the squared correlation                                                                                                                                                                    bound directly to the cycle                                                    the potential for a CoMFA study.
   application to test sets.                                                          coefficient (R2) is 0.82. Such a high correlation suggests                                                                                           Figure 5: FBSS Alignment of Steroids
                                                                                      that there is a significant relationship between molecular                                                                                                  (Hydrogen-Suppressed)                                                     Table 3: Classification of Melatonin Receptor                           The field-based alignment generates statistical models and drug-
              Figure 1: The Basic CoMFA Method                                        similarity and quality of the derived PLS model.                                                                                                                                                                                                       Antagonists
                                                                                                                                                                                                                                   Grid        Optimum          SECV           Q2
                                                                                                                                                                                                                                                                                                                                                                                                     design ideas that are consistent with those obtained using manual
                                                                                                                                                                                                                                 Spacing/Å    Components                                                    Sicsic et al. explored many alignment paradigms before developing an                     alignment procedures. It can be argued that a user would not want
It is proposed that FBSS can be used to align chemical structures as an                                               0.9
                                                                                                                                                                                                                                    1.0           3             0.466         0.866                         optimum CoMFA model. The FBSS procedure used compound 12 as a                            FBSS to generate an overlay identical (or as close to manual) as
                                                                                         Cross-Validated R2 (CoMFA)


initial step in a CoMFA analysis. The experiments discussed in this paper                                             0.7
                                                                                                                                                                                                                                                                                                            reference, as it was the most active inhibitor in the series and in the                  possible, but rather a non-obvious alternative overlay. However,
relate to the application of FBSS to aligning structures from previous
                                                                                                                                                                                                                                    R2             F             SE           pr-R2
                                                                                                                                                                                                                                                                                                            absence of any additional information may be the best starting point for                 where manual alignment is difficult or not possible, the results here
                                                                                                                      0.4                                                                                                          0.982        233.102         0.170         0.917
CoMFA experiments. In each case, models have been generated using                                                     0.3
                                                                                                                                                                                                                                                                                                            field-based alignment. The best literature model removed compounds                       suggest that FBSS is a viable alternative.
procedures taken from the original source (including, where possible,                                                 0.1                                                                                                                                                                                   14,18,47 and 48 as outliers for reasons explained within the original
provided alignments) as well as from FBSS-generated superpositions. The                                                0                                                                                                             Table 1: CoMFA Model from FBSS Alignment
                                                                                                                            0   0.1      0.2   0.3        0.4        0.5         0.6   0.7   0.8    0.9                                                                                                     paper. Our model was developed from co-ordinates supplied by the
models have been evaluated in terms of their robustness (given by Q2) and                                                                            Mean Molecular Similarity
                                                                                                                                                                                                               Although it is straightforward to manually align the steroids, it is common practice to      authors in which these compounds were already omitted. The test set of               Future work
their predictivity (given by the predictive R2 when applied to the test set).             Figure 3: FBSS Mean Molecular Similarity plotted                                                                                                                                                                  9 structures was taken from across the range of chemical families
                                                                                                                                                                                                               test any new 3D-QSAR technique using this data set. If the new method fails to                                                                                                     We will study data sets that have no obvious manual alignment. In
                                                                                         against CoMFA model’s Cross-Validated R2 for FBSS                                                                     produce a significant model using such simple data and alignment techniques, then it         expressed in the training set.                                                         these cases, we hope FBSS will produce a useful overlay for direct
                                                                                                           Alignment                                                                                           may not be worth pursuing with further data sets.                                                                                                                                   use in a 3D-QSAR method or will suggest ideas for a potential
                                                                                                                                                                                                                                                                                                            The statistics from the original CoMFA model are given in Table 4,                     manual alignment.
Calculation of Field-Based Overlap                                                    CoMFA Methods                                                                                                            A manual alignment of the CBG set provides the CoMFA model given in Table 2.                 while the CoMFA model generated by the FBSS alignment is presented
                                                                                                                                                                                                               Graphical examples of the fields that can be generated through FBSS are presented in         in Table 5. Rigorous aggregate reorientation was performed on the                     Incorporation of flexibility into the GA will be realised with the
and Similarities                                                                      CoMFA was performed using the QSAR and Advanced                                                                          Figure 6.                                                                                    manual alignment using a 1Å grid spacing, as the original CoMFA                        introduction of low-energy conformers through systematic or
                                                                                      CoMFA modules contained within SYBYL version 6.4 [4].                                                                                                                                                                 model was described using a coarse 2Å lattice-spacing.                                 random conformational searching algorithms.
The process of calculating the molecular fields within FBSS using                     Except where directly specified the default CoMFA                                                                                            Grid        Optimum          SECV           Q2
approximate Gaussian functions, and the subsequent determination of                   parameters provided with the software have been applied.                                                                                   Spacing/Å    Components
                                                                                                                                                                                                                                    1.0            2            0.450         0.870                                     Grid           Optimum             SECV              Q2
molecular similarity using the Carbo index are detailed in an earlier                                                                                                                                                                                                                                                 Spacing/Å       Components
publication by this group [1].                                                        Corticosteroid-Binding Globulin                                                                                                                                                                                                    1.0               5               0.613           0.720                 Important Note: FBSS results were compiled with no further
                                                                                                                                                                                                                                    R2             F             SE           pr-R2
                                                                                                                                                                                                                                   0.930         126.4          0.320         0.840                                                                                                              attempts to optimise the Q2 value produced from the CoMFA model,
                                                                                      Ligands : A CoMFA Model                                                                                                                                                                                                             R2                F               SE             pr-R2
                                                                                                                                                                                                                                                                                                                                                                                                 through modification of the lattice surrounding the superposed
                                                                                                                                                                                                                                  Table 2: CoMFA Model from the Manual Alignment                                         0.930             222             0.248           0.730
                                                                                      Developed Using FBSS Alignments                                                                                                                                                                                                                                                                            molecules, or variable selection procedures such as GOLPE [6] :
                                                                                                                                                                                                                                                                                                                    Table 4: CoMFA Model J from Original Melatonin                               procedures often employed in a CoMFA analysis.
                                                                                                                                                                                                                                                                                                                  CoMFA Paper [5] (after aggregate reorientation in a lattice
                                                                                      The CBG steroid set [2], was the first set of structures used
                                                                                                                                                                                                                                                                                                                               with a 1.0 Å grid spacing).
                                                                                      to validate the CoMFA method, and are often referenced as
FBSS Parameters for Molecular                                                         a benchmark against which new methods of analysis in 3D                                                                                                                                                                                                                                                    References
Alignment                                                                             QSAR can be compared. The data set consists of 31
                                                                                                                                                                                                                                                                                                                       Grid           Optimum             SECV              Q2
                                                                                      steroids that show binding affinity toward both                                                                                                                                                                                Spacing/Å       Components                                                  1. Drayton, S.K.; Edwards, K.; Jewell, N.E.; Turner, D.B.; Wild, D.J.; Willett, P.;
                                                                                      testosterone-binding globulin (TeBG) and corticosteroid-                                                                                                                                                                          1.0              5                0.704            0.717                    Wright, P.M. and Simmons, K. in
The FBSS algorithm allows the alignment of structures based on the                    binding globulin (CBG). The training set consists of 21                                                                                                                                                                                                                                                    2. Cramer, R.D., III; Patterson, D.E.; Bunce, J.D. J.Am.Chem.Soc. 1988, 110, 5959-
                                                                                                                                                                                                                                                                                                                         R2                F               SE              pr-R2                    5967.
overlap of electrostatic, steric or lipophilic fields. In addition, these fields      structures, with an additional 10 compounds reserved for                                                                                                                                                                                                                                                   3. Quantum Chemistry Program Exchange, Creative Arts Building 181, Indiana
                                                                                                                                                                                                                                                                                                                        0.981             407             0.179            0.547
can be used in any combination. An extensive phase of testing has led us              the test set (although these compounds are provided with                                                                                                                                                                                                                                                      University, Bloomington, Indiana 47405, USA.
to believe that, where other guiding factors are not present, the best                only CBG binding data). The popularity of this data set has                                                                                                                                                                 Table 5: CoMFA Model using FBSS-derived Alignment                              4. Tripos, Inc. 1699 South Hanley Road, St. Louis, Missouri 63144-2913, USA.
results are obtained by applying FBSS with all three fields simultaneously                                                                                                                                                                                                                                                                                                                       5. Sicsic, S.; Serraz, I.; Andrieux, J.; Bremont, B.; Mathe-Allainmat, M.; Poncet, A.;
                                                                                      led to its inclusion in the SYBYL software release, as part
                                                                                                                                                                                                                                                                                                                                                                                                    Shen, S.; Langlois, M. J.Med.Chem. 1997, 40, 5, 739-748.
(hereafter known as ‘All Fields’). In such a case, the resulting similarity is        of the CoMFA tutorial.                                                                                                                                                                                                                                                                                     6. Baroni, M.; Costantino, G.; Cruciani, G.; Riganelli, D.; Valigi, R.; Clementi, S.
                                                                                                                                                                                                                                                                                                            The CoMFA models for both the manual and FBSS-derived
taken from an average of all the fields and their overlap.                                                                                                                                                                                                                                                  alignments are displayed as contour plots within SYBYL. It is                           Quant.Struct-Act. Relat. 1993, 12, 9-20.
                                                                                      In the original literature, one of the ligands with the highest                                                                                                                                                       interesting to note that similar regions of CoMFA field are displayed
The GA parameters used to derive the alignments are shown in Figure 2.                CBG affinity (deoxycortisol) was used as the template                                                                                                                                                                 for each type of plot, demonstrating consistency between the models                      1. Krebs Institute for Biomolecular Research
It should be noted that FBSS was run 75 consecutive times, with the best              molecule. The superposition was based on a least-squares                                                                                                                                                              and validating the FBSS alignment. The Sicsic et al. model is shown                           Department of Information Studies
single result (determined as the orientation which generates the greatest             fit onto the carbon atoms of the template within the steran                                                                                                                                                           in Figure 7 and the FBSS-aligned CoMFA model in Figure 8.                                     University of Sheffield
molecular similarity between each pair of compounds) being reported. In               skeleton. The FBSS alignments (Figure 5) were also                                                                                                                                                                                                                                                                  Western Bank, Sheffield, UK
database searching, FBSS is normally only applied once per compound                   generated using deoxycortisol as a reference structure. The                                                                                                                                                                                                                                                         S10 2TN
due to time constraints. However, with many fewer structures considered               steroid compounds (after thorough checking and structure-
in a CoMFA experiment, multiple runs are possible.                                                                                                                                                                                                                                                                                                                                                   2. Zeneca Agrochemicals
                                                                                      correction by members of the group) were assigned semi-                                                                                                                                                                                                                                                             Jealotts Hill Research Station
                                                                                      empirical MOPAC [3] PM3 charges and aligned to the                                                                                                                                                                                                                                                                  Bracknell, Berkshire, UK
The GA has the capacity for flexible searching, using simple                          reference structure using the GA. During the prediction of                                                                                                                                                                                                                                                          RG42 6ET
conformational rules encoded within the chromosome. It has been found                 the test set activities from the PLS model, compound 31
that the RIGID methods provide the best CoMFA models, provided that                   was omitted from the analysis as an outlier (this has been                                                                                                                                                                                                                                                     Acknowledgements
the initial structures are of suitable conformation; attempts to incorporate          done by a number of groups).                                                                                                                                                                                                                                                                                   This work was funded by a BBSRC CASE award
flexibility are ongoing, as noted in the conclusions.                                                                                                                                                                                                                                                                                                                                                with Zeneca Agrochemicals.
                                                                                      Contour plots summarising CoMFA PLS results using                                                                                                                                                                          Figure 7: Steric and Electrostatic (coefficient*stdev) plots
                                                                                      FBSS-derived alingments are given in Figures 4 and 5. The                                                                                                                                                                                                                                                      Thanks also to Dr. David Wilton and Dr. Ansgar Schuffenhauer for
                                                                                                                                                                                                                     Figure 6: FBSS Electrostatic (top left), Steric (top right) and Hydrophobic (bottom)                        for the Manual Alignment                                            useful input at all stages
                                                                                      statistical details are provided in Table 1.                                                                                         molecular fields for Aldosterone, an example of the steroid training set                     (Contour levels of 10.0 and 90.0 are used)                                   of this project.

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