The problem of predicting ligands of a protein is one of the most challenging problems in biolochemistry, with profound implications for pharmaceutical chemistry and the discovery of protein function. Many approaches have been developed for protein–ligand binding prediction, the most prominent being molecular docking. The number of protein structures in the Protein Data Bank is increasing rapidly and approaches that use information from existing experimental protein-ligand complexes - an alternative to the molecular docking approach - are becoming increasingly important. In these alternative approaches, it is assumed that similar binding sites are likely to bind similar ligands and in such cases, a known ligand of one protein can be transposed to a similar binding site in another protein that was previously not known to bind this ligand. Such transposition of ligands, especially between non-homologous proteins, depends on accurate alignments of 3D patterns of amino acid functional groups in the proteins’ binding sites. Such alignments are not detectable by standard sequence or structure alignment approaches. The ProBiS-ligands web server predicts binding of ligands to a protein structure. Starting with a protein structure or binding site, ProBiS-ligands first identifies template proteins in the Protein Data Bank that share similar binding sites. Based on the superimpositions of the query protein and the similar binding sites found, the server then transposes the ligand structures from those sites to the query protein. Such ligand prediction supports many activities, e.g. drug repurposing. The ProBiS-ligands web server, an extension of the ProBiS web server, is open and free to all users at http://probis.cmm.ki.si/ligands. The ProBiS-ligands web server provides an interactive environment in which users can explore the predicted protein–ligand complexes. One of the major advantages of ProBiS-ligands is that it allows transposition of ligands between protein structures irrespective of protein folding and with no prior knowledge of binding sites. This allows an established ligand, e.g. a drug, to be seen in a new perspective in which binding to other proteins, not hitherto recognized as targets, can be recognized. Repurposing of established drugs follows directly from this. We envision that the construction of accurate models of known ligands in binding sites will enable design of more specific ligands.

ProBiS-ligands: A web server for prediction of ligands by examination of protein binding sites

249th National Meeting (2015)

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