Discovery of potentially deleterious sequence variants is important and has wide implications for research and generation of new hypotheses in human and veterinary medicine, and drug discovery. The GenProBiS web server maps sequence variants to protein structures from the Protein Data Bank (PDB), and further to protein–protein, protein–nucleic acid, protein–compound, and protein–metal ion binding sites. The concept of a protein–compound binding site is understood in the broadest sense, which includes glycosylation and other post-translational modification sites. Binding sites were defined by local structural comparisons of whole protein structuresusing the Protein Binding Sites (ProBiS) algorithm and transposition of ligands from the similar binding sites found to the query protein using the ProBiS-ligands approach with new improvements introduced in GenProBiS. Binding site surfaces were generated as three-dimensional grids encompassing the space occupied by predicted ligands. The server allows intuitivevisual exploration of comprehensively mapped variants, such as human somatic mis-sense mutations related to cancer and nonsynonymous single nucleotide polymorphisms from 21 species, within the predicted binding sites regions for about 80 000 PDB protein structures using fast WebGL graphics. The GenProBiS web server is open and free to all users at http://genprobis.insilab.org.
COBISS.SI-ID: 3897736
Elevated expression of the immunoproteasome has been associated with autoimmune diseases, inflammatory diseases, and various types of cancer. Selective inhibitors of the immunoproteasome are not only scarce, but also almost entirely restricted to peptide-based compounds. Herein, we describe nonpeptidic reversible inhibitors that selectively block the chymotrypsin-like (ß5i) subunit of the human immunoproteasome in the low micromolar range. The most potent of the reversibly acting compounds were then converted into covalent, irreversible, nonpeptidic inhibitors that retained selectivity for the ß5i subunit. In addition, these inhibitors discriminate between the immunoproteasome and the constitutive proteasome in cell-based assays. Along with their lack of cytotoxicity, these data point to these nonpeptidic compounds being suitable for further investigation as ß5i-selective probes for possible application in noncancer diseases related to the immunoproteasome.
COBISS.SI-ID: 4050545
Proteins often exist only as apo structures (unligated) in the Protein Data Bank, with their corresponding holo structures (with ligands) unavailable. However, Apo proteins may not represent the amino-acid residue arrangement upon ligand binding well, which is especially problematic for molecular docking. We developed the ProBiS-CHARMMing web interface by connecting the ProBiS (http://probis.cmm.ki.si) and CHARMMing (http://www.charming.org) web servers into one functional unit that enables prediction of protein−ligand complexes and allows for their geometry optimization and interaction energy calculation. The ProBiS web server predicts ligands(small compounds, proteins, nucleic acids, and single atom ligands) thatmay bind to a query protein. This is achieved by comparing its surface structure against a nonredundant database of protein structures and finding those that have binding sites similar to that of the query protein. Existing ligands found in the similar binding sites are then transposed to the query according to predictions from ProBiS. The CHARMMing web server enables, among other things, minimization and potential energy calculation fora wide variety of biomolecular systems, and it is used here to optimize the geometry of the predicted protein−ligand complex structures using the CHARMM force field and to calculate their interaction energies with the corresponding query proteins. We show how ProBiS-CHARMMing can be used to predict ligands and their poses for a particular binding site, and minimize the predicted protein−ligand complexes to obtain representations of holoproteins. The ProBiS-CHARMMing web interface is freely available for academic users at http://probis.nih.gov.
COBISS.SI-ID: 5806106
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 is open and free to all users at http://probis.nih.gov
COBISS.SI-ID: 5514010
Graph-Theoretical Matrices in Chemistry presents a systematic survey of graph-theoretical matrices and highlights their potential uses. This comprehensive volume is an updated, extended version of a former bestseller featuring a series of mathematical chemistry monographs. In this edition, nearly 200 graph-theoretical matrices are included. Most of the graph-theoretical matrices presented have been used as sources of molecular descriptors usually referred to as topological indices. They are particularly concerned with a special class of graphs that represents chemical structures involving molecules. Due to its multidisciplinary scope, this book will appeal to a broad audience ranging from chemistry and mathematics to pharmacology. https://www.crcpress.com/Graph-Theoretical-Matrices-in-Chemistry/Janezic-Milicevic-Nikolic-Trinajstic/9781498701150
COBISS.SI-ID: 1537505220