Reviews in Computational Chemistry Volume 18
Reviews in Computational Chemistry Volume 18
Reviews in Computational Chemistry Volume 18
- No tags were found...
Create successful ePaper yourself
Turn your PDF publications into a flip-book with our unique Google optimized e-Paper software.
100<br />
80<br />
60<br />
40<br />
20<br />
Application of Scor<strong>in</strong>g Functions <strong>in</strong> Virtual Screen<strong>in</strong>g 67<br />
COX-2<br />
0<br />
1 2 3 4 5 10 20 30 50 100<br />
FlexX score<br />
PLP<br />
ScreenScore<br />
0<br />
1 2 3 4 5 10 20 30 50 100<br />
scor<strong>in</strong>g function by <strong>in</strong>clud<strong>in</strong>g directed hydrogen bond<strong>in</strong>g terms, 63 which may<br />
lead to a similarly robust scor<strong>in</strong>g function as ScreenScore.<br />
Another example where the balance between H-bond<strong>in</strong>g and hydrophobic<br />
contributions is important <strong>in</strong>volves the performance of the knowledgebased<br />
scor<strong>in</strong>g function DrugScore. 92 The estrogen receptor b<strong>in</strong>d<strong>in</strong>g site is a<br />
large lipophilic cavity with acceptor groups at either end that can form hydrogen<br />
bonds with ligand hydroxyl groups as present <strong>in</strong> the agonists 1 and 2 or<br />
the antagonists 3 and 4 (Figure 6). The narrow b<strong>in</strong>d<strong>in</strong>g pocket and relatively<br />
rigid nature of the ligands restra<strong>in</strong>s possible b<strong>in</strong>d<strong>in</strong>g modes significantly.<br />
Accord<strong>in</strong>gly, it can be assumed that FlexX is capable of generat<strong>in</strong>g reasonable<br />
solutions likely to be <strong>in</strong> agreement with experiment. Therefore we can expect<br />
the present example to represent a valuable test for scor<strong>in</strong>g functions. For both<br />
agonists and antagonists, lipophilic <strong>in</strong>teractions largely determ<strong>in</strong>e the b<strong>in</strong>d<strong>in</strong>g<br />
energy. The majority of antagonists, however, differ from the agonists <strong>in</strong> an<br />
additional side cha<strong>in</strong> bear<strong>in</strong>g a tertiary am<strong>in</strong>o group. This difference is<br />
reflected <strong>in</strong> the bound structures of the receptor. In the agonist-bound state<br />
the b<strong>in</strong>d<strong>in</strong>g pocket is not accessible to solvent, whereas <strong>in</strong> the antagonistbound<br />
state it opens up and allows the positively charged antagonist side cha<strong>in</strong><br />
to form a salt bridge with the carboxylate group of Glu 351. Agonists should<br />
b<strong>in</strong>d equally well to both forms of the receptor. A 7500 compound subset from<br />
the World Drug Index (WDI) and a library of 20 agonists and 16 antagonists<br />
were docked <strong>in</strong>to both agonist (PDB code 1ere) and antagonist (PDB code<br />
1err) forms of the receptor. FlexX scores obta<strong>in</strong>ed from both structures are<br />
plotted aga<strong>in</strong>st each other <strong>in</strong> Figure 6(a). Due to the large contribution of<br />
100<br />
80<br />
60<br />
40<br />
20<br />
Neuram<strong>in</strong>idase<br />
Figure 5 Results of seed<strong>in</strong>g experiments on two targets with three different scor<strong>in</strong>g<br />
functions. In both graphs, the accumulated percentages of active compounds are plotted<br />
aga<strong>in</strong>st the percentage of the total ranked library. The smooth exponential curve <strong>in</strong> each<br />
graph corresponds to the hypothetical case of no enrichment and assumes a random<br />
order<strong>in</strong>g of the database.