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
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