A chemoinformatics approach to identify bioisosteric scaffold replacements in compounds of PubChem bioassays [Elektronische Ressource] / vorgelegt von Kerstin Höhfeld

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Informations

• Publié par: friedrich-alexander-universitat_erlangen-nurnberg
• Publié le: 01 janvier 2010
• Nombre de lectures: 19
• Langue: Deutsch
• Poids de l'ouvrage: 3 Mo

Extrait

A Chemoinformatics Approach to
Identify Bioisosteric Scaffold
Replacements in Compounds of
PubChem Bioassays



















Der Naturwissenschaftlichen Fakultät
der Friedrich-Alexander-Universität Erlangen-Nürnberg
zur
Erlangung des Doktorgrades



vorgelegt von

Kerstin Höhfeld



aus Wipperfürth






























Als Dissertation genehmigt von der Naturwissenschaftlichen
Fakultät der Universität Erlangen-Nürnberg


Tag der mündlichen Prüfung: 28.10.2009
Vorsitzender der Promotionskommission: Prof. Dr. Eberhard Bänsch
Erstberichterstatter: Prof. Dr. Timothy Clark
Zweitberichterstatter: Prof. Dr. Harald Gröger
List of Contents

List of Contents

Lists of Figures and Tables ............................................................................................................ ii
Zusammenfassung ........................ 1
Abstract ......................................... 4
Introduction .................................................................................................... 6
Methods ....... 11
Search Method ........................................................................................................................ 11
Selection of Examples ............ 19
Scaffold Alignment .............................................................................................................. 20
Results and Discussion ............... 25
Results of Systematic Search ................................................................................................. 25
Special Scaffold Replacements .......................... 28
Selection of Examples ............................................................................................................ 31
Factor Xa ............................................................................................................................ 34
Pyruvate Kinase Assay (Assay ID 361) .............. 37
Protein Kinase A (Assay ID 548) ........................ 44
Protein Tau (Assay ID 596) ................................................................................................ 52
Steroidogenic Factor 1 (Assay ID 600) .............. 55
Estrogen Receptor-Beta (Assay ID 733) ............................................................................ 57
Factor XIa (Assay ID 846) .................................. 62
Factor XIIa (Assay ID 852) ................................................................. 66
Hydroxysteroid (17-Beta) Dehydrogenase 4 (Assay ID 893) ............. 69
Acetylcholine Muscarinic M1 Receptor (Assay ID 944) ..................................................... 74
Thrombin (Assay ID 1215).................................................................. 76
Neuropeptide Y Receptor Y2 (Assay ID 1272)................................... 82
B-cell Lymphoma 2 Family proteins (Assay ID 1320) ........................ 84
Signal Transducer and Activator of Transcription (STAT) Family (Assay ID 1397) ........... 86
Conclusions ................................................................................................................................. 88
Scaffold Properties and Substituent Orientation 88
Evaluation Scheme ............................................................................................................. 89
Chemical Descriptors .............. 93
General Discussion ................. 99
Outlook .................................................................................................................................. 101
Acknowledgement ..................... 104
References 105
Appendix ................................................................................................................................... 112
i List of Figures


List of Figures

Figure 1 Example of a successful scaffold hopping for a Factor Xa Inhibitor. .............................. 6
Figure 2 Example of exit vectors. .................................................................................................. 7
Figure 3 Example of the longest shortest path in a molecule and resulting exterior atoms. ....... 13
Figure 4 Example of two common substructures (orange) of two molecules, compounds
648322 and 660787 from assay ID 548. ....................................................................... 15
Figure 5 Connecting part between two common substructures: [CH2][S]. . 15
Figure 6 Scheme of search workflow. ......................................................................................... 17
Figure 7 Start and endpoint of two according pairs of exit vectors and the resulting
PyMOL fit of the corresponding four atoms (RMS: 0.275 Å). ....................................... 19
Figure 8 Left: Example of the Cresset field points representation for compound 648322.
Right: The ParaSurf isodensity surface of the same molecule (CID 648322). ............. 21
Figure 9 Scheme for investigation of selected examples. ........................................................... 23
Figure 10 Histogram of connecting structure sizes, all results of the search method are
considered (n=685). ...................................................................... 26
Figure 11 Histogram of replacement types, only replacements with an atom number
greater than zero of both molecules are concerned (n=410). ....... 26
Figure 12 Histogram of size differences of according connecting structures, all results of
the search method are considered (n=684). ................................................................. 27
Figure 13 Molecule with original substituents (left) and scaffold saturated with methyl
groups (right). ................................................................................................................ 31
Figure 14 Adenosintriphosphat (ATP). ........................ 47
Figure 15 Two different presentations of the same docking pose of compound 648322 in
the crystal structure of protein 2F7E. ............................................................................ 48
Figure 16 GOLD docking results for compound 648322 (orange) and 660787 (turquoise)
in the protein with PDB code 2FE7. .............. 49
Figure 17 Best FieldAlign result for compound 648322-S (orange) and 660787-S
(turquoise). .................................................................................................................... 49
Figure 18 Compound 124727 (green) and 648322 (turquoise). .................. 50
Figure 19 Evaluation scheme. ..................................................................................................... 90


ii
List of Tables

List of Tables

Table 1: List of selected PubChem bioassays that show at least one example mentioned
in the chapter Results and Discussion. ......................................................................... 12
Table 2 Short result of a MySQL table with information stored to each exterior atom. .............. 14
Table 3 Top 10 replacements of connecting structures found by the search method. ............... 28
Table 4 Replacements for amides ([C]=O[NH]) in all results of the PubChem Search. ............. 29
Table 5 Identical replacements in different assays. .................................................................... 30
Table 6 Tanimoto coefficients of selected examples, the column match no is introduced to
make a difference between several matches of one assay. ......... 32
Table 7 Structures of two Factor Xa inhibitors with activity information. ..................................... 34
Table 8 FieldAlign results for the two selected Factor Xa inhibitors. .......... 35
Table 9 ParaFit results shown together with the FieldAlign result for the Factor Xa
inhibitors. ....................................................................................................................... 36
Table 10 Match of compounds 657882 and 893238 and activity information. ........................... 37
Table 11 FieldAlign results for match of compound 657882-S and 893238-S. .......................... 38
Table 12 ParaFit alignment and FieldAlign result for compound 657882-S and 893238-S........ 38
Table 13 Matched compounds 619837 and 657882 with activity information. ........................... 39
Table 14 Best results of FieldAlign and ParaFit for 619837-S and 657882-S. 39
Table 15 Matched compound 346489 and 2999802 and activity information. 40
Table 16 FieldAlign results for compounds 2999802-S and 346489-S. ..................................... 41
Table 17 Best results of FieldAlign and ParaFit for compounds 2999802-S and 346489-S. ..... 41
Table 18 Match of 2357867 and 3236025 with activity information. ........... 42
Table 19 FieldAlign results for compounds 2357867-S and 3236025-S. ................................... 42
Table 20 ParaFit result with options IEL plus surface for compounds 2357867-S and
3236025-S. .....................