Abstract
We describe a novel freely available web server Base of Bioisosterically Exchangeable Replacements (BoBER), which implements an interface to a database of bioisosteric and scaffold hopping replacements. Bioisosterism and scaffold hopping are key concepts in drug design and optimization, and can be defined as replacements of biologically active compound’s fragments with other fragments to improve activity, reduce toxicity, change bioavailability or to diversify the scaffold space. Our web server enables fast and user-friendly searches for bioisosteric and scaffold replacements which were obtained by mining the whole Protein Data Bank. The working of the web server is presented on an existing MurF inhibitor as example. BoBER web server enables medicinal chemists to quickly search for and get new and unique ideas about possible bioisosteric or scaffold hopping replacements that could be used to improve hit or lead drug-like compounds.
Highlights
Bioisosterism and scaffold hopping are key concepts in the lead optimization stages of drug discovery [1, 2]
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 Protein Data Bank (PDB) mining approach [14]
We developed a new web server BoBER that enables the prediction of bioisosteric replacements given a query fragment or query small molecule as input based on our knowledge-based method that uses binding sites superimposition to identify possible bioisosteric and scaffold hopping replacements from existing ligands
Summary
Bioisosterism and scaffold hopping are key concepts in the lead optimization stages of drug discovery [1, 2]. Fragments occupying the same geometric space are considered as potentially bioisosterically replaceable Another method, KRIPO [11] quantifies similarities of binding site subpockets based on optimized pharmacophore based fingerprints, and enables both intra- and inter-family comparisons of proteins. 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 [15,16,17,18,19], which enables identification of locally similar binding sites irrespective of proteins’ folds or amino acid sequences. The web server was tested in the Chrome and Firefox web browsers
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