One important class of proteins found in eukaryotic domain of biology is chaperonins. These proteins serve to assist the preparation of other proteins via assisted folding as well as other mechanisms. These types of proteins have emerged as potential targets for antifungal therapeutics since, without their function, many other essential cellular processes fail. A “new” antifungal drug target is Heat Shock protein 90 (HSP90), a protein which weighs about 90 kilodaltons. Due to their structural similarity, it is difficult for small molecules to target the fungal HSP90 selectivity. However, a recent deposit into the PDB shows an example of a highly selective, biologically active HSP90 inhibitor. The inhibitor was co-crystallized with the Nucleotide Binding Domain (NBD) of HSP90 and is selective based on differences in flexibility of the human and fungal versions of the NBD of HSP90. This phenomenon was previously observed when the fungal selectivity of certain Cytochrome P450 inhibitors was investigated.
Naturally, this structure invites the investigation of whether other small molecules can bind to and inhibit fungal HSP90 via interactions with the NBD. This structure, which pertains genetically to Cryptococcus neoformans, was thus used for virtual screening to identify molecules which can bind similarly to the co-crystal ligand and exert a fungistatic effect. The co-crystal ligand is a resorcylate amino pyrazole. Initial results show that the majority of the ligand’s favorable interactions within the binding site are hydrophobic in nature, however there is one hydrogen bond with aspartate 79. Overall, the binding pose was reproduced successfully through the DOCK6 flexible ligand docking method indicating reliability in the algorithm with respect to this system.
Approximately 4 million compounds were scored from a “molecular weight” based tranche from the ZINC database. Amongst the top compounds from the DOCK6 screen included multiple amides linking heterocyclic rings. This makes sense since the cognate ligand is also an amide linking heterocyclic rings. The top compounds are predicted to form the same hydrogen bond to aspartate 79 as the co-crystal ligand. The docking scores for the top compounds presented are significantly better than the co-crystal ligand, although for compound 1 and 3, most of this improved interaction profile is hydrophobic in nature (data not presented). A total of approximately 4 million compounds were screened and only the top 0.2 % of docking scores were saved for further analysis, meaning there are about 8,000 potential HSP90 inhibitors derived from this docking study. If you are interested in analyzing more of these results or if you’d like to test some of these compounds, send me an email. HSP90 inhibitors may provide a novel and potent mechanism of action to help patients with fungal infection.
Control docking experiment and predicted binding poses of top scoring molecules
