Scaffold Hopping and Bioisosteric Replacements Based on Binding Site Alignments

Abstract

Bioisosteric replacements and scaffold hopping play an important role in modern drug discovery and design, as they enable the change of either a core scaffold or substitutes in a drug structure, thereby facilitating optimization of pharmacokinetic properties and patenting, while the drug retains its activity. A new knowledge-based method was developed to obtain bioisosteric or scaffold replacements based on the extensive data existing in the Protein Data Bank. The method uses all-against-all ProBiS-based protein superimposition to identify ligand fragments that overlap in similar binding sites and could therefore be considered as bioisosteric replacements. The method was demonstrated on a specific example of drug candidate -a nanomolar butyrylcholinesterase inhibitor, on which bioisosteric replacements of the three ring fragments were performed. The new molecule containing bioisosteric replacements was evaluated virtually using AutoDock Vina; a similar score for the original and the compound with replacements was obtained, suggesting that the newly designed bioisostere compound might retain the potency of the original inhibitor.

BoBER: web interface to the base of bioisosterically exchangeable replacements

“…As described previously [ 14 ], the process of bioisosteric replacement identification is started by using ProBiS to superimpose holo protein structures from the PDB. In this process, small-molecule ligand binding sites that have similar three-dimensional amino-acid arrangements are superimposed.…”

“…The BoBER web server enables intuitive and fast searching of bioisosteric replacements for drug-like molecules in the previously prepared database of bioisosteric fragments. The web interface enables the user to broaden the search for bioisosteric replacements by implementing Rules 1–5 also described previously [ 14 ], which rely on the concept of join and core atoms. These are defined as: join atoms are atoms at which the rotatable covalent bonds are broken during the fragmenting process; core atoms are all atoms that are not join atoms.…”

“…a bond to a carbon atom can only be formed if it currently has less than four bonds, where bonds to hydrogen atoms are ignored. In ([ 14 ]) we also define Rule 5, which states that Rules 1–4 can be sequentially combined, and which is implicitly used in the BoBER web server.…”

“…In this work we present Base of Bioisosterically Exchangeable Replacements (BoBER), a new web server for identification of bioisosteric and scaffold hopping replacements based on our PDB mining approach [ 14 ]. In this approach, bioisosteric replacements are identified using local binding site alignment algorithm ProBiS [ 15 – 19 ], which enables identification of locally similar binding sites irrespective of proteins’ folds or amino acid sequences.…”

“…It seeks for similar local spatial arrangements of physico-chemically similar surface functional groups in binding sites, enabling the detection of replaceable fragment pairs between distantly related protein structures. ProBiS was used to superimpose holo binding sites from the entire PDB, and pairs of bioisosterically replaceable fragments were collected in the BoBER database [ 14 ]. The advantage of our method, which takes into account local neighborhood of fragments, is that it enables the distinction between different binding pockets in proteins with similar overall sequence identity, while recognizing similar binding pockets in proteins with very different sequences.…”