ABSTRACT
Recent years have seen a tremendous increase in the generation and deposition of x-ray structures of carbonic anhydrase inhibitor (CAI) complexes. For more than 45 years, carbonic anhydrase (CA) isozymes have been a well-known class of interesting targets for pharmaceutical research. So far, most rationally designed CAIs have been based on anchors, as zinc-binding groups, directly linked to a cyclic carbon moiety, but it is known that the more general motif X-SO2NH2 as present in sulfamides (X = N) and sulfamates (X = O) binds to the catalytical Zn(II) ion of CA isozymes as well. The increasing body of crystallographically determined proteinligand complexes provides information about the frequent occurrence of alternative
patterns. One of the diisopropylidene moieties of topiramate is replaced by a cyclic sulfate group in RWJ-37947. Solely based on bonding topology, it is tempting to assume similar binding properties of both resulting in similar binding modes. However, experiments show the opposite: RWJ-37947 adopts a totally different ligand pose in the active site of hCA II compared to topiramate. This chapter presents an automated docking procedure that generates conformations of CAIs close to the crystal structure. It is surprising that using as a selection criterion the frequency of how often a particular docking solution is generated, current docking algorithms such as AutoDock can reproduce correctly the observed binding modes for topiramate and RWJ-37947 in their respective crystallographically determined enzymeinhibitor complexes.
