A study of 30 flavonoid derivatives, taken from PubChem database and docked on flavonoid 3-O-glucosyltransferase 3HBF, next submitted to a QSAR study, performed within a hypermolecule frame, to model ...their LD50 values, is reported. The initial set of molecules was split into a training set and the test set (taken from the best scored molecules in the docking test); the predicted LD50 values, computed on similarity clusters, built up for each of the molecules of the test set, surpassed in accuracy the best model. The binding energies to 3HBF protein, provided by the docking step, are not related to the LD50 of these flavonoids, more protein targets are to be investigated in this respect. However, the docking step was useful in choosing the test set of molecules.
Motivation: Exploitation of locally similar 3D patterns of physicochemical properties on the surface of a protein for detection of binding sites that may lack sequence and global structural ...conservation. Results: An algorithm, ProBiS is described that detects structurally similar sites on protein surfaces by local surface structure alignment. It compares the query protein to members of a database of protein 3D structures and detects with sub-residue precision, structurally similar sites as patterns of physicochemical properties on the protein surface. Using an efficient maximum clique algorithm, the program identifies proteins that share local structural similarities with the query protein and generates structure-based alignments of these proteins with the query. Structural similarity scores are calculated for the query protein's surface residues, and are expressed as different colors on the query protein surface. The algorithm has been used successfully for the detection of protein–protein, protein–small ligand and protein–DNA binding sites. Availability: The software is available, as a web tool, free of charge for academic users at http://probis.cmm.ki.si Contact: dusa@cmm.ki.si Supplementary information: Supplementary data are available at Bioinformatics online.
ProBiS (Protein Binding Sites), a local structure-based comparison algorithm, is used in the new ProBiS-Fold web server to annotate human structures from the AlphaFold database without a ...corresponding structure in the Protein Data Bank (PDB) to discover new druggable binding sites. The ProBiS algorithm is used to compare each query protein structure predicted by the AlphaFold approach with the protein structures from the PDB to identify similarities between known binding sites found in the PDB and yet unknown binding sites in the AlphaFold database. Ligands bound in these identified similar PDB sites are then transferred to each query protein from the AlphaFold database, and binding sites are identified as ligand clusters on an AlphaFold protein. Small molecule binding sites are assigned druggability scores based on the similarity of their ligands to known drugs, allowing them to be ranked according to their perceived and actual potential for drug development. ProBiS-Fold provides interactive and downloadable binding sites for the entire human structural proteome, including more than 3000 new druggable binding sites that have no corresponding structure in the PDB, taking into account AlphaFold’s model quality, to enable protein structure–function relationship studies and pharmaceutical drug discovery research. The web server is freely accessible to academic users at http://probis-fold.insilab.org.
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 structures using 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 intuitive visual exploration of comprehensively mapped variants, such as human somatic mis-sense mutations related to cancer and non-synonymous 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.
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.
Generalization of an earlier algorithm has led to the development of new local structural alignment algorithms for prediction of protein−protein binding sites. The algorithms use maximum cliques on ...protein graphs to define structurally similar protein regions. The search for structural neighbors in the new algorithms has been extended to all the proteins in the PDB and the query protein is compared to more than 60 000 proteins or over 300 000 single-chain structures. The resulting structural similarities are combined and used to predict the protein binding sites. This study shows that the location of protein binding sites can be predicted by comparing only local structural similarities irrespective of general protein folds.
SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2, represents a new strain of
. In the closing 2019 to early 2020 months, the virus caused a global pandemic of COVID-19 disease. We ...performed a virtual screening study in order to identify potential inhibitors of the SARS-CoV-2 main viral protease (3CL
or M
). For this purpose, we developed a novel approach using ensemble docking high-throughput virtual screening directly coupled with subsequent Linear Interaction Energy (LIE) calculations to maximize the conformational space sampling and to assess the binding affinity of identified inhibitors. A large database of small commercial compounds was prepared, and top-scoring hits were identified with two compounds singled out, namely 1-(R)-2-(1,3-benzimidazol-2-yl)-1-pyrrolidinyl-2-(4-methyl-1,4-diazepan-1-yl)-1-ethanone and ({(S)-1-(1H-indol-2-yl)methyl-3-pyrrolidinyl}methyl)amino(5-methyl-2H-pyrazol-3-yl)formaldehyde. Moreover, we obtained a favorable binding free energy of the identified compounds, and using contact analysis we confirmed their stable binding modes in the 3CL
active site. These compounds will facilitate further 3CL
inhibitor design.
Identification of conserved waters in protein structures is a challenging task with applications in molecular docking and protein stability prediction. As an alternative to computationally demanding ...simulations of proteins in water, experimental cocrystallized waters in the Protein Data Bank (PDB) in combination with a local structure alignment algorithm can be used for reliable prediction of conserved water sites. We developed the ProBiS H2O approach based on the previously developed ProBiS algorithm, which enables identification of conserved water sites in proteins using experimental protein structures from the PDB or a set of custom protein structures available to the user. With a protein structure, a binding site, or an individual water molecule as a query, ProBiS H2O collects similar proteins from the PDB and performs local or binding site-specific superimpositions of the query structure with similar proteins using the ProBiS algorithm. It collects the experimental water molecules from the similar proteins and transposes them to the query protein. Transposed waters are clustered by their mutual proximity, which enables identification of discrete sites in the query protein with high water conservation. ProBiS H2O is a robust and fast new approach that uses existing experimental structural data to identify conserved water sites on the interfaces of protein complexes, for example protein–small molecule interfaces, and elsewhere on the protein structures. It has been successfully validated in several reported proteins in which conserved water molecules were found to play an important role in ligand binding with applications in drug design.
d-Alanine:d-alanine ligase (Ddl), an intracellular bacterial enzyme essential for cell wall biosynthesis, is an attractive target for development of novel antimicrobial drugs. This study focused on ...an extensive evaluation of two families of Ddl inhibitors encountered in our previous research. New members of both families were obtained through similarity search and synthesis. Ellipticines and 9-acridinylamines were both found to possess inhibitory activity against Ddl from Escherichia coli and antimicrobial activity against E. coli and Staphylococcus aureus. Ellipticines with a quaternary methylpyridinium moiety were the most potent among all studied compounds, with MIC values as low as 2mg/L in strains with intact efflux mechanisms. Antimicrobial activity of the studied compounds was connected to membrane damage, making their development as antibacterial drug candidates unlikely unless analogues devoid of this nonspecific effect can be discovered.
Resveratrol is a polyphenol known for its antioxidant and anti-inflammatory properties, which support its use as a treatment for variety of diseases. There are already known connections of ...resveratrol to chemoprevention of cancer because of its ability to prevent tumor initiation and inhibit tumor promotion and progression. Resveratrol is also believed to be important in cardiovascular diseases and neurological disorders, such as Alzheimer’s disease. Using an inverse molecular docking approach, we sought to find new potential targets of resveratrol. Docking of resveratrol into each ProBiS predicted binding site of >38 000 protein structures from the Protein Data Bank was examined, and a number of novel potential targets into which resveratrol was docked successfully were found. These explain known actions or predict new effects of resveratrol. The results included three human proteins that are already known to bind resveratrol. A majority of proteins discovered however have no already described connections with resveratrol. We report new potential target human proteins and proteins connected with different organisms into which resveratrol can dock. Our results reveal previously unknown potential target human proteins, whose connection with cardiovascular and neurological disorders could lead to new potential treatments for variety of diseases. We believe that our research could help in future experimental studies on revestratol bioactivity in humans.
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