Reviews in Computational Chemistry Volume 18

O O
S
HN
S
Application of Scoring Functions in Virtual Screening 73
O
O
S
NH2 O
S S S
O
O
O
S
NH2 O
O
S
NH2 group. A set of 3314 compounds passed these requirements. In the second
filtering step, the known CAII inhibitor dorzolamide 8 was used as a template
onto which all potential candidates were flexibly superimposed by means of the
program FlexS. 172 The top-ranking compounds from this step were then
docked into the binding site with FlexX 64–66 taking into account four conserved
water molecules in the active site. The top-ranking 13 hits were chosen
for experimental testing. Nine of these compounds showed activities below
1 mM, and the sulfonamides 9 and 10 (Figure 10) have Ki values below 1 nM.
The de novo design of inhibitors of the bacterial enzyme DNA gyrase is
another example for a successful application of structure-based virtual screening.
14 DNA gyrase is a well-established antibacterial target. 216 It is an essential,
prokaryotic type II topoisomerase with no mammalian counterpart
involved in the vital processes of DNA replication, transcription, and recombination.
DNA gyrase catalyzes the ATP-dependent introduction of negative
supercoils into bacterial DNA as well as the decatenation and unknotting of
DNA. The enzyme consists of two subunits A and B with the active enzyme
being an A2B2 complex. Subunit A of DNA gyrase is involved in DNA breakage
and reunion, whereas the B subunits catalyze the hydrolysis of ATP. Quinolones
(e.g., the now famous ciprofloxacin), which inhibit DNA gyrase by
binding to the subunit A, are successfully used as broad-spectrum antibacterial
agents in the clinic. Unfortunately, resistance to quinolones emerged some
time ago. The two other classes of DNA gyrase inhibitors, cyclothialidines
and coumarins (e.g., novobiocin), bind to the ATP binding site of subunit B.
Novobiocin was clinically used against Staphylococcus aureus, but it suffers
from toxicity effects and resistance against it is developing rapidly. As demonstrated
by the cyclothialidines, this type of resistance can be overcome. Unfortunately,
the cyclothialidines have insufficient in vivo activities due to a class
specific rapid and extensive glucuronidation of the essential phenol moiety.
To overcome the limitations of known DNA gyrase inhibitors, a new
drug discovery project was inititated at Roche. Searching for novel inhibitors
by screening the Roche compound library provided no suitable lead structures.
O
N
O
N
O
8 9 10
Figure 10 Inhibitors of carbonic anhydrase II. Compounds 9 and 10 are subnanomolar
inhibitors identified through virtual screening. Compound 8 is the marketed drug
dorzolamide.