Virtual Exploration of Chemical Space by Database Generation
Virtual Exploration of Chemical Space by Database Generation
Virtual Exploration of Chemical Space by Database Generation
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<strong>Virtual</strong> <strong>Exploration</strong> <strong>of</strong> <strong>Chemical</strong> <strong>Space</strong> <strong>by</strong> <strong>Database</strong><br />
<strong>Generation</strong><br />
Jean-Louis Reymond<br />
University <strong>of</strong> Berne<br />
Switzerland<br />
1
The <strong>Chemical</strong> Universe <strong>Database</strong> (GDB)<br />
> <strong>Chemical</strong> <strong>Space</strong> Travel<br />
Swiss National Science Foundation<br />
Tobias Fink<br />
2
The <strong>Chemical</strong> Universe Project<br />
HN<br />
O<br />
NH<br />
S<br />
J. Lederberg, C. Djerassi et al. J. Am. Chem. Soc. 1969, 91, 2973<br />
T. Fink et al. Angew. Chem. Int. Ed. 2005, 44, 1504-1508, , J. Chem. Inf. Model. 2007, 47, 342-353<br />
3
Structure Generator<br />
Graphs from GENG<br />
I. Graph Selection<br />
II: Structure <strong>Generation</strong><br />
III: Filters<br />
IV: Stereoisomers<br />
843,335<br />
↓<br />
15,726<br />
↓<br />
276,220<br />
↓<br />
1.7 billion<br />
↓<br />
26.4 million<br />
GDB<br />
4
I. Graph Selection<br />
Table 1. Graph selection table. Each graph corresponds to a saturated hydrocarbon.<br />
Nodes Graphs a Passed Topo I b Passed Topo II c Planar Graphs d Unstrained Graphs e with unsaturations<br />
1 1 1 1 1 1 1<br />
2 1 1 1 1 1 3<br />
3 2 2 2 2 2 4<br />
4 6 4 4 4 4 13<br />
5 21 8 8 8 8 33<br />
6 78 20 20 20 20 123<br />
7 353 57 57 57 57 445<br />
8 1’929 199 194 194 194 1'956<br />
9 12’207 780 712 708 705 8'863<br />
10 89’402 3’600 2’893 2’845 2’822 43'443<br />
11 739’335 19’215 12’575 12’169 11’912 221'336<br />
Total 843’335 23’887 16’467 16’009 15’726 276'220<br />
a generated <strong>by</strong> the program GENG using a maximum connectivity <strong>of</strong> 4. b The Topo I filters eliminates any graph with a<br />
node present in two different 3 or 4-membered ring. c The Topo II filter eliminates graphs with a tetravalent bridgehead<br />
in a small ring. d Non-planar graphs cannot be drawn in a plane without crossing edges, e.g. 3.<br />
5
Tetrahedrane<br />
I. Graph Selection<br />
Claus Benzol<br />
K 3,3 Graph<br />
Tricyclo[2.2.2.2]decane<br />
6
Count<br />
350<br />
300<br />
250<br />
200<br />
150<br />
100<br />
50<br />
0<br />
1<br />
6<br />
Steric Energy Distribution over Ringsystems<br />
11<br />
16<br />
21<br />
26<br />
I. Graph Selection<br />
31<br />
36<br />
41<br />
46<br />
51<br />
56<br />
61<br />
66<br />
71<br />
Highest Atomic Contribution [kcal/mol]<br />
76<br />
81<br />
86<br />
91<br />
96<br />
7
Graph automorphism<br />
> Multiple bonds<br />
– no allenes<br />
– no DB at tetravalent nodes<br />
– no DB at bridgeheads<br />
– no TB at tri- or tetravalent nodes<br />
– no TB inside rings smaller than 9<br />
– no duplicates (symmetry)<br />
> Elements<br />
II. Structure <strong>Generation</strong><br />
– C, N, O, F at chemically meaningful nodes (valency rules)<br />
1.7 billion "molecules"<br />
276,220<br />
8
III. Filters<br />
> "Problematic" heteroatom constellations (X-X)<br />
> Hydrolytically labile FG's<br />
> Tautomers + aromaticity<br />
OH<br />
OH<br />
OH<br />
N<br />
H<br />
O<br />
N<br />
N<br />
OH<br />
NH 2<br />
O<br />
F<br />
O O O<br />
F (O, N)<br />
O<br />
OH<br />
-CHO + -NH 2<br />
9
Structure Generator<br />
Graphs from GENG<br />
I. Graph Selection<br />
II: Structure <strong>Generation</strong><br />
III: Filters<br />
IV: Stereoisomers<br />
843,335<br />
↓<br />
15,726<br />
↓<br />
276,220<br />
↓<br />
1.7 billion<br />
↓<br />
26.4 million<br />
GDB<br />
10
IV. Stereoisomers<br />
– Nourse, J. G.; Carhart, R. E.; Smith, D. H.; Djerassi, C. Exhaustive<br />
<strong>Generation</strong> <strong>of</strong> Stereoisomers for Structure Elucidation. J. Am. Chem. Soc.<br />
1979, 101, 1216-1223.<br />
11
Table 2. Overview <strong>of</strong> the structure generation process.<br />
Nodes Graphs a Generated b<br />
GDB Overview<br />
Accepted c<br />
Unique<br />
Tautomers<br />
(GDB) d<br />
All Tautomers Stereoisomers e<br />
1 1 4 4 4 4 4<br />
2 1 10 9 9 9 9<br />
3 2 52 20 20 21 20<br />
4 4 332 80 80 88 87<br />
5 8 2’294 357 352 397 469<br />
6 20 18’066 1’906 1’850 2’135 2’911<br />
7 57 154’542 10’953 10’568 12’438 19’904<br />
8 194 1’445’073 69’563 66’706 79’899 153’601<br />
9 705 14’213’741 464’402 444’313 540’002 1’258’963<br />
10 2’822 146’004’340 3’259’036 3’114’041 3’827’907 10’898’065<br />
11 11’912 1’558’491’448 23’875’101 22’796’628 28’240’425 98’645’474<br />
Total 15’726 1’720’329’902 27’681’431 26’434’571 32’703’325 110’979’507<br />
log N = a x n 2<br />
12
13<br />
GDB <strong>by</strong> Graph<br />
Monocycli<br />
c<br />
43%<br />
Polycyclic<br />
1%<br />
Tricyclic<br />
9%<br />
Bicyclic<br />
32%<br />
Acyclic<br />
15%<br />
1<br />
10<br />
100<br />
1'000<br />
10'000<br />
100'000<br />
1<br />
250<br />
500<br />
750<br />
100<br />
125<br />
150<br />
175<br />
200<br />
225<br />
250<br />
275<br />
300<br />
325<br />
350<br />
375<br />
400<br />
425<br />
450<br />
475<br />
500<br />
525<br />
550<br />
575<br />
Graphs<br />
Number <strong>of</strong> compounds<br />
Acyclic<br />
Monocyclic<br />
Bicyclic<br />
Tricyclic<br />
Polycyclic<br />
CH 4
Most Prolific Graphs<br />
Bicyclic<br />
32%<br />
Tricyclic<br />
9%<br />
Polycyclic<br />
1%<br />
94'903 cpds 64'641cpds 48'836 cpds 12'983 cpds<br />
Acyclic<br />
15%<br />
Monocycli<br />
c<br />
43%<br />
14
GDB <strong>by</strong> Elemental Composition<br />
Table 3. Number <strong>of</strong> compounds in GDB as a function <strong>of</strong> elemental composition (rows) and number <strong>of</strong> heavy atoms<br />
(columns).<br />
Number <strong>of</strong> heavy atoms<br />
Elemental<br />
composition<br />
1 2 3 4 5 6 7 8 9 10 11 Total<br />
C 1 3 4 12 29 102 347 1'468 6'413 30'582 152'117 191'078<br />
N 1 0 0 0 0 0 0 0 0 0 0 1<br />
O 1 1 0 0 0 0 0 0 0 0 0 2<br />
F 1 1 0 0 0 0 0 0 0 0 0 2<br />
CN 0 1 6 22 91 443 2'255 12'832 76'063 472'756 3'049'435 3'613'904<br />
CO 0 2 5 19 74 338 1'671 9'302 54'733 337'024 2'164'860 2'568'028<br />
CF 0 1 3 12 39 151 622 2'954 14'598 77'225 429'664 525'269<br />
CNO 0 0 2 11 82 526 3'578 24'858 176'888 1'299'010 9'819'032 11'323'987<br />
CNF 0 0 0 2 17 122 818 5'594 39'052 279'803 2'059'976 2'385'384<br />
COF 0 0 0 2 18 126 809 5'437 37'148 260'489 1'883'487 2'187'516<br />
CNOF 0 0 0 0 2 42 468 4'401 39'910 358'528 3'236'049 3'639'400<br />
Total 4 9 20 80 352 1'850 10'568 66'846 444'805 3'115'417 22'794'620 26'434'571<br />
15
Novelty vs. RDB<br />
> Ring systems<br />
> Stereochemistry<br />
> Physico-chemical properties<br />
> Compound classes<br />
> Drugs and leads<br />
IV: Stereoisomers<br />
GDB Analysis<br />
GDB<br />
16
RDB = 63'857 cpds<br />
Novelty vs. RDB<br />
– organic molecules up to 11 atoms from PubChem, ChemACX, ChemSCX,<br />
NCI open database, Merck Index<br />
26'464<br />
– Sulfur (14'048)<br />
– Acyl halides etc. (7'782)<br />
– S, P, Si (3'787)<br />
– Allenes etc. (629)<br />
– Topology (218)<br />
RDB<br />
37'393<br />
GDB<br />
26.4 million<br />
17
Ring Systems<br />
Number <strong>of</strong> 4-membered rings<br />
Number <strong>of</strong> 3-membered rings 0 1 2 Total<br />
0 124 [3] 189 [60] 103 [67] 416 [130]<br />
1 225 [50] 238 [177] 20 [19] 483 [246]<br />
2 201 [88] 55 [48] - 256 [136]<br />
3 53 [26] - - 53 [26]<br />
Total 603 [167] 482 [285] 123 [86] 1'208 [538]<br />
18
Ring Sytems<br />
– Chiral: 677 (367 unknown)<br />
– Achiral: 455 (150 unknown)<br />
– Both 76 (21 unknown)<br />
> Acyclic graphs<br />
– Chiral: 166 (all known)<br />
– Achiral: 143 (all known)<br />
> All graphs<br />
Stereochemistry<br />
– Chiral: 12'771<br />
– Achiral: 2'955 19.2 million<br />
Chiral<br />
7.1 million<br />
Achiral<br />
134’390 (including tartaric acid!)<br />
Fraction <strong>of</strong> SCU Compounds<br />
100%<br />
75%<br />
50%<br />
25%<br />
0%<br />
Chiral<br />
Achiral<br />
1 3 5 7 9 11 13 15 17 19<br />
Number <strong>of</strong> heavy atoms<br />
19
Stereochemistry<br />
Table 5. Number <strong>of</strong> stereocenters vs. number <strong>of</strong> stereoisomers for GDB compounds.<br />
Number <strong>of</strong> stereocenters a<br />
Number <strong>of</strong><br />
stereoisomers b 0 1 2 3 4 5 6 7 8 9 10 Total<br />
1 3’805’751 c<br />
0 127’959 e<br />
0 25’340 186 10’245 68 1’125 58 66 3’970’798<br />
2 2’193’503 d 4’023’245 1’160’206 189’290 317’283 33’036 88’602 7’945 7’488 228 158 8’020’984<br />
3 2’481 d<br />
0 13’182 0 2’493 0 115 0 31 0 0 18’302<br />
4 572’362 d 1’664’209 3’524’711 2’137’679 380’906 320’836 53’880 43’573 3’240 889 5 8’702’290<br />
5 0 0 0 0 61 0 14 0 0 0 0 75<br />
6 229 d<br />
38 1’860 1’253 422 87 256 14 3 0 0 4’162<br />
7 0 0 0 0 6 0 0 0 0 0 0 6<br />
8 49’980 d<br />
188’701 733’641 1’869’820 1’265’196 362’856 93’685 19’829 3’794 130 0 4’587’632<br />
10 62 d<br />
0 300 0 1’537 52 521 12 26 0 0 2’510<br />
12 0 0 142 164 510 44 4 0 0 0 0 864<br />
16 991 d<br />
3’822 29’787 165’346 443’339 286’119 108’252 8’965 1’096 89 0 1’047’806<br />
20 4 d<br />
0 0 0 6 0 18 0 1 0 0 29<br />
24 0 0 0 0 14 107 0 0 0 0 0 121<br />
32 19 d<br />
0 118 2’208 11’041 41’237 17’192 5’605 134 1 0 77’555<br />
36 0 0 0 0 0 0 42 0 0 0 0 42<br />
64 0 0 0 0 0 186 1’209 0 0 0 0 1’395<br />
Total 6’625’382 5’880’015 5’591’906 4’365’760 2’448’154 1’044’746 374’035 86’011 16’938 1’395 229 26’434’571<br />
a) A stereocenter is defined as an atom at which the interchange <strong>of</strong> two groups produces a stereoisomer, with the<br />
exception <strong>of</strong> E/Z isomers. b) Total number <strong>of</strong> stereoisomers resulting from a compound. c) Molecules containing no<br />
stereocenters and no E/Z double bonds. d) Molecules resulting in E/Z isomers only.<br />
20
Stereochemistry<br />
21
10 stereocenters<br />
1 stereoisomer<br />
Stereochemistry<br />
6 stereocenters<br />
64 stereoisomers<br />
22
Novelty vs. RDB<br />
> Ring systems<br />
> Stereochemistry<br />
GDB Analysis<br />
> Physico-chemical properties<br />
> Compound classes<br />
> Drugs and leads<br />
IV: Stereoisomers<br />
GDB<br />
23
Frequency x10 3<br />
7000000<br />
6000000<br />
5000000<br />
4000000<br />
3000000<br />
2000000<br />
1000000<br />
> MW ~ 153 Dal<br />
> H-bond Acceptors ~ 3<br />
> H-bond Donors ~ 1.5<br />
> log P, NRB, TPSA<br />
0<br />
0<br />
1<br />
2<br />
3<br />
4<br />
Physico-chemical properties<br />
10000<br />
5<br />
8000<br />
6000<br />
4000<br />
2000<br />
6<br />
Number <strong>of</strong> Rotatable Bonds<br />
0<br />
0<br />
2<br />
4<br />
7<br />
6<br />
8<br />
8<br />
Frequency x10 3<br />
Frequency x10 3<br />
4500000<br />
4000000<br />
3500000<br />
3000000<br />
2500000<br />
2000000<br />
1500000<br />
1000000<br />
500000<br />
0<br />
2500000<br />
2000000<br />
1500000<br />
1000000<br />
500000<br />
0<br />
-12.0<br />
0<br />
-10.5<br />
12<br />
-9.0<br />
24<br />
-7.5<br />
36<br />
-6.0<br />
48<br />
-4.5<br />
60<br />
-3.0<br />
72<br />
-1.5<br />
0.0<br />
logP<br />
84<br />
96<br />
1.5<br />
4000<br />
3000<br />
2000<br />
1000<br />
108<br />
6000<br />
5000<br />
4000<br />
3000<br />
2000<br />
1000<br />
0<br />
-12<br />
-9<br />
-6<br />
-3<br />
0<br />
3<br />
6<br />
9<br />
3.0<br />
120<br />
4.5<br />
132<br />
6.0<br />
144<br />
Topological Polar Surface Area [A 3 ]<br />
0<br />
0<br />
28<br />
56<br />
84<br />
112<br />
7.5<br />
140<br />
156<br />
9.0<br />
168<br />
168<br />
196<br />
24
RO5 (Lipinski )<br />
RO3 (Congreve)<br />
Physico-chemical properties<br />
MW<br />
≤ 500<br />
≤ 300<br />
logP<br />
≤ 5<br />
≤ 3<br />
Lipinski et al., Adv. Drug. Deliv. Rev. 1997, 23, 3<br />
Congreve et al., Drug Discov. Today 2003, 8, 876<br />
HBD<br />
≤ 5<br />
≤ 3<br />
HBA<br />
≤ 10<br />
≤ 3<br />
All structures OK<br />
Half <strong>of</strong> all structures OK<br />
NRB<br />
≤ 3<br />
TPSA<br />
≤ 60 Å 2<br />
25
Rdb<br />
GDB<br />
Property <strong>Space</strong><br />
DMU<br />
26
Novelty vs. RDB<br />
> Ring systems<br />
> Stereochemistry<br />
> Physico-chemical properties<br />
> Compound classes<br />
> Drugs and leads<br />
IV: Stereoisomers<br />
GDB Analysis<br />
GDB<br />
27
AC<br />
d<br />
N<br />
p<br />
d<br />
where<br />
=<br />
=<br />
=<br />
⎧1<br />
δ ij = ⎨<br />
⎩0<br />
N<br />
= ∑∑ δ ⋅<br />
i=<br />
1 j=<br />
1<br />
Number <strong>of</strong><br />
if<br />
if<br />
N<br />
Autocorrelation Descriptors<br />
( p ⋅ p )<br />
Considered topological<br />
Atomic property<br />
d<br />
d<br />
ij<br />
ij<br />
i<br />
=<br />
≠<br />
atoms<br />
d<br />
d<br />
j<br />
d<br />
distance<br />
(Kronecker Delta)<br />
Partial σ- and π-charges<br />
Atomic polarizability<br />
Topological steric effect index<br />
Atomic number<br />
Identity function<br />
0-7 bonds<br />
Moreau, G.; Broto, P. Autocorrelation <strong>of</strong> Molecular Structures. Application to SAR Studies.<br />
Nouv. J. Chim. 1980, 4, 757-764.<br />
28
48-dimensional AC vector<br />
> 200x200 neurons, toroidal<br />
> 1’000’000 GDB molecules<br />
Kohonen Map<br />
> 100 molecules/epoch, 250’000 epochs<br />
> map 26.4 million<br />
> Color code for properties<br />
29
1 10 100 1000 10000<br />
Occupancy<br />
1 10 100 1000 1000030
Heavy atoms:<br />
< 7 7 8 9 10 11<br />
Molecular size<br />
Mixed Empty<br />
1 10 100 1000 1000031
Compound Classes<br />
Heteroaromatic Aromatic Fused heterocyclic<br />
Fused Carboc. Heterocyclic Carbocyclic<br />
Heteroacyclic Carboacyclic Mixed Empty<br />
1 10 100 1000 1000032
Lead-likeness and Chirality<br />
Heteroaromatic Aromatic Fused heterocyclic<br />
Carbocyclic Heterocyclic Carbocyclic<br />
Heteroacyclic Carboacyclic Mixed Empty<br />
Chiral<br />
Achiral Empty<br />
Lead-like<br />
33<br />
Mixed<br />
Mixed<br />
Not lead-like Empty
OH<br />
O<br />
O<br />
O<br />
Fragrances<br />
Heteroaromatic Aromatic Fused heterocyclic<br />
Fused Carboc Heterocyclic Carbocyclic<br />
Heteroacyclic Carboacyclic Mixed Empty<br />
HO<br />
HO<br />
O<br />
O<br />
O<br />
O<br />
O<br />
34
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
Camphor Analogs<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
35
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
Rose Oxide Analogs<br />
O O<br />
O<br />
O<br />
O O<br />
O<br />
O<br />
O<br />
O O<br />
O<br />
O<br />
O O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
36
Novelty vs. RDB<br />
> Ring systems<br />
> Stereochemistry<br />
> Physico-chemical properties<br />
> Compound classes<br />
> Drugs and leads<br />
IV: Stereoisomers<br />
GDB Analysis<br />
GDB<br />
37
O<br />
H 2N<br />
N<br />
H<br />
39<br />
(Paracetamol)<br />
44<br />
(GABA)<br />
O<br />
O<br />
O<br />
49<br />
(Brevicomin)<br />
OH O<br />
OH<br />
HO<br />
H 2N<br />
Known Drugs in GDB<br />
OH<br />
40<br />
(Pregabalin)<br />
O<br />
NH 2<br />
O<br />
45<br />
(Glutamate)<br />
O<br />
50<br />
(Carvon)<br />
OH<br />
H 2N<br />
NH 2<br />
41<br />
(Amantadine)<br />
46<br />
(Dopamine)<br />
OH<br />
51<br />
(Menthol)<br />
OH<br />
OH<br />
O<br />
H<br />
F<br />
O<br />
N<br />
H<br />
NH<br />
O<br />
42<br />
(Fluorouracil)<br />
HO<br />
O<br />
47<br />
(Niacin)<br />
52<br />
(Benzaldehyde)<br />
N<br />
O<br />
H<br />
F<br />
F<br />
F<br />
F<br />
O F<br />
F<br />
43<br />
(Desflurane)<br />
O<br />
O<br />
48<br />
(Frontalin)<br />
53<br />
(Cinnamaldehyde )<br />
38
O<br />
N<br />
N<br />
NH<br />
N<br />
N<br />
N<br />
H<br />
F<br />
F<br />
N<br />
O<br />
N N<br />
HN<br />
N HN<br />
H<br />
N<br />
OH<br />
NH 2<br />
Bayesian <strong>Virtual</strong> Screening<br />
Heteroaromatic Aromatic Fused heterocyclic<br />
Carbocyclic Heterocyclic Carbocyclic<br />
Heteroacyclic Carboacyclic Mixed Empty<br />
OH<br />
N<br />
HN<br />
OH<br />
37 38 39<br />
O<br />
OH<br />
N<br />
N<br />
31 32 33<br />
34 35 36<br />
F<br />
F<br />
N<br />
OH<br />
N<br />
NH<br />
37<br />
32<br />
31<br />
35<br />
34<br />
39<br />
Kinase Inhibitors<br />
GPCR ligands<br />
Ion-channel modulators<br />
36<br />
33<br />
38<br />
39
The <strong>Chemical</strong> Universe <strong>Database</strong> (GDB)<br />
> <strong>Chemical</strong> <strong>Space</strong> Travel<br />
Swiss National Science Foundation<br />
R. Van Deursen, J.-L. Reymond ChemMedChem 2007, 2, 636-640<br />
Ruud van Deursen<br />
40
<strong>Chemical</strong> <strong>Space</strong> Travel<br />
> Move continuously via nearest neighbours<br />
> Unknown space<br />
> Structural vs. property space<br />
A<br />
B<br />
n<br />
41
A<br />
<strong>Chemical</strong> <strong>Space</strong> as a Graph<br />
B<br />
Nearest neighbour mutations<br />
Atom type exchange<br />
Atom inversion<br />
Atom removal<br />
Atom addition<br />
Bond saturation<br />
Bond unsaturation<br />
Bond rearrangement<br />
42
Selection<br />
Selector<br />
<strong>Space</strong>ship<br />
Start A<br />
Generator<br />
Mutants<br />
Ranking Target B<br />
Ranked Mut.<br />
No Target B found<br />
Yes<br />
Stop<br />
Store in DB<br />
43
A<br />
A<br />
<strong>Space</strong>ship<br />
B<br />
mutation selection<br />
mutation<br />
B<br />
F(c) = (T SF(target, c) x T PF(target, c)) 5<br />
A<br />
A<br />
selection<br />
B<br />
B<br />
44
A<br />
Trajectory Libraries<br />
B<br />
Filters<br />
"crude" possible<br />
A<br />
B<br />
45
Compound Formula mass n [a]<br />
Trajectory Examples (1)<br />
Nearest<br />
neighbours<br />
Steps from CH 4 [b]<br />
With<br />
aromatic [c]<br />
Steps to<br />
N [d] MeOH [b]<br />
Cubane C 8H 8 104 8 12 - 6'638 7 994<br />
Fluorouracil C 4H 3FN 2O 2 130 9 16 9* 2'456 7* 560<br />
Metheneamine C6H12N4 140 10 12 - 6'157 9 1'768<br />
3-Tetrazene-2carboximidamide<br />
C2H6N10 170 12 12<br />
-<br />
4'685 11* 2'007<br />
Aspirine C9H8O4 180 13 15 8(1) 2'567 12 2'582<br />
9-Ethyl-carbazole C 14H 13N 197 15 n.f. [e] 20(2) 20'501 16 5'357<br />
Vitamin H C 10H 16N 2O 3S 244 16 18* - 27'161 14* 6'304<br />
VX (van) C 11H 26NO 2PS 267 16 21 - 29'460 14* 3'954<br />
Adenosine C 10H 13N 5O 4 267 19 n.f. [e] 25(2) 23'680 19* 13'639<br />
β-estradiol C 18H 24O 2 272 20 23 15(2) 43'089 20 19'067<br />
Retinal C 20H 28O 284 21 23 - 45'176 19* 15'100<br />
Morphine C 17H 19NO 3 285 21 26 18(2) 69'113 20* 16'247<br />
Aspartame C 14H 18N 2O 5 294 21 303 16(2) 34'172 20* 11'430<br />
Cocaine C 17H 21NO 4 303 22 n.f. [e] 20(2)* 70'807 22 17'993<br />
N [d]<br />
46
Compound Formula mass n [a]<br />
Trajectory Examples (2)<br />
Nearest<br />
neighbours<br />
Steps from CH4 [b]<br />
With<br />
aromatic [c]<br />
Steps to<br />
N [d] MeOH [b]<br />
Tetrodotoxine C 11H 17N 3O 8 319 22 28 - 106'158 20* 16'757<br />
Sucrose C 12H 22O 11 342 23 25* - 67'052 21 19'552<br />
Penicillin G C 16H 18N 2O 4S 334 23 n.f. [e] 20(2) 70'497 23* 15'748<br />
Strychnine C 21H 22N 2O 2 332 25 n.f. [e] 26(2) 176'721 25 32'479<br />
Papaverin C 20H 21NO 4 339 25 n.f. [e] 25(3) 53'099 25 28'449<br />
Colchicine C 22H 25NO 6 399 29 37 32(3) 136'519 28 33'592<br />
Calcitriol C 27H 44O 3 417 30 37* - 298'327 28* 65'595<br />
Dipicrylamine C 12H 5N 7O 12 439 31 n.f. [e] 21(2) 21'015 26 13'950<br />
Tetracycline C 22H 24N 2O 8 428 31 36 30(1) 173'734 30 34'883<br />
Vitamin K C 31H 46O 2 451 33 55 42(3) 411'107 32* 77'337<br />
Epothilone C 27H 41NO 6S 508 35 n.f. [e] 62(4) 709'250 34* 75'219<br />
Vitamin E C 29H 50O 2 531 38 71 40(2) 443'477 37* 140'017<br />
Reserpine C 33H 40N 2O 9 609 44 n.f. [e] 68(5) 286'342 62 230'646<br />
Taxotere C 45H 55NO 15 808 58 n.f. [e] 74(4) 1'128'960 57* 304'172<br />
N [d]<br />
47
From: To:<br />
Cubane<br />
Aspirine<br />
Cross-Trajectories<br />
VX<br />
Cubane - 10 18<br />
Adenosine<br />
23<br />
(1)<br />
Aspirine 10* - 14 21 15 16 24 22 22 33<br />
VX 13<br />
17<br />
(1)<br />
-<br />
31<br />
(1)<br />
Adenosine 17* 27 18* - 14 15 24 23 27* 29<br />
Sucrose 18*<br />
22<br />
(1)<br />
22*<br />
29<br />
(1)<br />
Sucrose<br />
19<br />
18<br />
Penicillin G<br />
18<br />
(1)<br />
15<br />
(1)<br />
- 25<br />
Penicillin G 19* 13* 14* 23 19* - 20 19* 21* 29<br />
Strychnine 21* 17* 20 26 22 16* - 30* 17* 22*<br />
Colchicine 27 22* 21 26 18 22 23 - 22* 21*<br />
Tetracycline 28* 20 25* 49 19 19* 16 28 - 17<br />
Vitamin K 30* 24* 30* 34* 28* 27* 19* 30* 22* -<br />
Strychnine<br />
18<br />
(1)<br />
21<br />
(1)<br />
26<br />
(1)<br />
Colchicine<br />
22<br />
(1)<br />
20<br />
(2)<br />
31<br />
(1)<br />
Tetracycline<br />
24<br />
(1)<br />
24*<br />
(1)<br />
25<br />
(1)<br />
Vitamin K<br />
26<br />
(1)<br />
25*<br />
(1)<br />
25<br />
(1)<br />
48
HO<br />
N O<br />
O<br />
NH 2<br />
OH<br />
AMPA ↔ CNQX<br />
14 ± 3<br />
16 ± 2<br />
O<br />
H<br />
O N N+<br />
O-<br />
O<br />
N<br />
H<br />
N<br />
49
N<br />
O<br />
N<br />
OH<br />
H 2N<br />
AMPA<br />
HO<br />
HN<br />
O<br />
O<br />
OH<br />
NH<br />
OH<br />
O<br />
O<br />
NH 2<br />
O O<br />
HO N<br />
O<br />
NH<br />
N<br />
NH 2<br />
O<br />
O<br />
N +<br />
-<br />
O<br />
O<br />
H<br />
N<br />
Trajectory<br />
O<br />
HO<br />
OH<br />
O<br />
NH 2<br />
O<br />
1 2 3 4<br />
OH<br />
N<br />
5 6 7 8<br />
O<br />
N<br />
H<br />
N O<br />
OH<br />
9 10 11<br />
N<br />
H<br />
O<br />
O<br />
HN<br />
O<br />
O<br />
O<br />
O<br />
OH<br />
NH<br />
NH<br />
O<br />
NH<br />
N<br />
NH 2<br />
O -<br />
N +<br />
O<br />
N<br />
OH<br />
HO<br />
O<br />
O<br />
O<br />
N<br />
H<br />
N<br />
N<br />
H<br />
O<br />
O<br />
NH<br />
N<br />
H<br />
CNQX<br />
OH<br />
N<br />
H<br />
N O<br />
OH<br />
O -<br />
N +<br />
O<br />
N<br />
50
AMPA-CNQX Libraries<br />
> AMPA → CNQX<br />
> CNQX → AMPA<br />
> Runaway from AMPA<br />
> Runaway from CNQX<br />
(500 runs)<br />
559,656 cpds<br />
(20 steps, 100 runs)<br />
152,916 cpds<br />
51
Rearrangement<br />
40%<br />
Bond type operations<br />
Desaturation: 0.735 ± 0.054<br />
Saturation: 0.437 ± 0.274<br />
Rearrangement: 0.512 ± 0.260<br />
Atom type operations<br />
Insertion: 0.788 ± 0.210<br />
Removal: 0.550 ± 0.268<br />
Identity: 1.000 ± 0.000<br />
Inversion: 0.768 ± 0.062<br />
Substitution: 0.726 ± 0.149<br />
Mutation Statistics<br />
Identity 1% 1% Inversion<br />
Desaturation 1% 7% Saturation<br />
24%<br />
13%<br />
13%<br />
Insertion<br />
Removal<br />
Substitution<br />
52
Docking<br />
Table 4. Average estimated binding energies <strong>by</strong> docking <strong>of</strong> trajectory compounds using AutoDock.<br />
Trajectory Ngenerated<br />
[a]<br />
NSelected SMILES<br />
[b]<br />
NStereoisomers BE (kcal/mol) [c]<br />
AMPA to CNQX 353'036 3’571 8’570 -8.8 ± 0.9<br />
CNQX to AMPA 206'622 2’051 5’754 -10.1 ± 1.0<br />
run-away from AMPA 91'417 992 7’586 -9.1 ± 0.9<br />
run-away from CNQX 61'499 974 5’751 -8.5 ± 0.9<br />
[a] Randomly selected structures (as SMILES codes) from the trajectory library. [b] All possible stereoisomers were<br />
generated using CORINA. [c] Average Binding Energy <strong>of</strong> the most stable bound conformation located <strong>by</strong> AutoDock.<br />
53
HO<br />
N O<br />
O<br />
NH 2<br />
OH<br />
Docking<br />
H<br />
N<br />
N<br />
H<br />
1 (BE = -10.4) 2 (BE = -9.3)<br />
HO<br />
H 2N<br />
O<br />
O<br />
OH<br />
3 (BE = -13.9)<br />
O<br />
O<br />
N<br />
NH 2<br />
O<br />
N+<br />
O-<br />
N<br />
54
1FTK.pdb<br />
Docking<br />
55
Docking, synthesis and testing<br />
> Expand GDB<br />
> Graphical user interface<br />
Outlook<br />
Swiss National Science Foundation<br />
56