Wilcken R. Nonclassical interactions in molecular recognition and their implications for targeted mutant rescue of the tumor suppressor protein p53 (Tubingen, 2011). - ОГЛАВЛЕНИЕ / CONTENTS

Навигация

Архив выставки новых поступлений | Отечественные поступления | Иностранные поступления | Сиглы
ОбложкаWilcken R. Nonclassical interactions in molecular recognition and their implications for targeted mutant rescue of the tumor suppressor protein p53: Diss. … Dr. rer. nat. - Tubingen: Eberhard-Karls Universitat, 2011. - [10], 267 p.: ill. - Bibliogr.: p.190-204.
 

Место хранения: 02 | Отделение ГПНТБ СО РАН | Новосибирск

Оглавление / Contents
 
1  Introduction ................................................. 2
   1.1  Structure-based drug design and quantum mechanics ....... 2
   1.2  The tumor suppressor p53 and the therapeutic concept
        of protein stabilization ................................ 3
   1.3  Thesis Objectives ....................................... 4
2  Halogen bonding and its implications for drug design ......... 8
   2.1  Nonclassical interactions in structure-based molecular
        design .................................................. 8
   2.2  Quantum chemical methodology ........................... 12
        2.2.1  Wavefunction-based approaches ................... 12
        2.2.2  Density functional theory ....................... 14
        2.2.3  Computational methodology ....................... 16
   2.3  Addressing backbone carbonyl oxygens by halogen bonds .. 20
        2.3.1  Energetics of the C-X...O=C halogen bond ........ 21
        2.3.2  Spatial behavior of XB - Bond distances ......... 32
        2.3.3  Spatial behavior of XB - a-hole directionality .. 34
        2.3.4  "Spatial behavior of XB - Spherical scans ....... 36
        2.3.5  Conclusion and application to molecular design .. 41
   2.4  Addressing methionine through directed sulfur-halogen
        bonds .................................................. 44
        2.4.1  Energetics of the C-X...S halogen bond .......... 45
        2.4.2  Spatial behavior of XB - Bond distances ......... 51
        2.4.3  Spatial behavior of XB - o-hole directionality .. 54
        2.4.4  Spatial behavior of XB - Spherical scans ........ 56
        2.4.5  Conclusion and application to molecular design .. 62
   2.5  Bfeyond Halogen Bonds: a-hole bonding involving
        cysteine and methionine ................................ 65
3  p53 Drug Discovery .......................................... 68
   3.1  Structure and Function of the tumor suppressor p53 ..... 68
        3.1.1  The p53 network ................................. 68
        3.1.2  Domain structure of p53 ......................... 70
        3.1.3  p53 mutations - from disruption of DNA binding
               to the β-sandwich mutants and Y220C ............. 73
   3.2  Concepts in p53 drug discovery ......................... 76
        3.2.1  Activation of p53 by inhibiting its negative
               regulation ...................................... 76
        3.2.2  Protein stabilization through pharmacological
               chaperones ...................................... 77
   3.3  Targeted mutant rescue of Y220C ........................ 79
        3.3.1  The discovery of PhiKan083 - Proof of
               Principle ....................................... 79
        3.3.2  Computational and biophysical methods ........... 81
        3.3.3  Biophysical Evaluation of PK083 derivatives as
               Y220C Stabilizers ............................... 94
        3.3.4  in silico and biophysical screening towards
               new scaffolds for protein stabilization ........ 111
        3.3.5  Focus on halogen bonding and design of a
               halogen-enriched fragment library yields
               p53-Y220C mutant stabilizers with
               unconventional binding modes ................... 125
        3.3.6  Further characterization of PK5174 and PK5176
               as next-generation p53 mutant stabilizers ...... 148
   3.4  Strategies towards targeted mutant rescue of R273H .... 156
        3.4.1  Methods - Modeling ............................. 156
        3.4.2  Modification proposals towards rescuing R273H .. 158
   3.5  Stabilization of wildtype p53 ......................... 161
        3.5.1  Virtual screening .............................. 161
        3.5.2  Biophysical testing ............................ 163
        3.5.3  Biophysical testing of PKX007 analogs .......... 166
4  QM-MD and DFT-D studies towards sampling the
   conformational complexity of the macrolactone
   Archazolid A ............................................... 170
   4.1  Introduction .......................................... 170
   4.2  Methods ............................................... 172
        4.2.1  Molecular Dynamics simulations ................. 172
        4.2.2  DFT-D studies .................................. 173
   4.3  Results ............................................... 173
        4.3.1  MD simulations ................................. 173
        4.3.2  DFT-D Calculations ............................. 174
   4.4  Discussion ............................................ 181
5  Summary / Zusammenfassung .................................. 184
6  Bibliography ............................................... 190
Appendix ...................................................... 205
   A  Additional 1H/15N-HSQC NMR spectra for carbazole
      compounds ............................................... 205
   B  Halogen-enriched fragment library ....................... 206
   C  Biophysical testing data of all next generation Y220C
      stabilizers ............................................. 218
   D  Syntheses of PK compounds with acetylene linker ......... 244
   E  Spectral data of PK compounds with acetylene linker ..... 247


Архив выставки новых поступлений | Отечественные поступления | Иностранные поступления | Сиглы
 


[О библиотеке | Академгородок | Новости | Выставки | Ресурсы | Библиография | Партнеры | ИнфоЛоция | Поиск | English]
  Пожелания и письма: www@prometeus.nsc.ru
© 1997-2019 Отделение ГПНТБ СО РАН (Новосибирск)
Статистика доступов: архив | текущая статистика
 

Документ изменен: Wed Feb 27 14:27:54 2019. Размер: 9,114 bytes.
Посещение N 641 c 29.09.2015