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.
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.
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.
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.
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.
SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2, represents a new pathogen from the family of Coronaviridae that caused a global pandemic of COVID-19 disease. In the absence of ...effective antiviral drugs, research of novel therapeutic targets such as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) becomes essential. This viral protein is without a human counterpart and thus represents a unique prospective drug target. However, in vitro biological evaluation testing on RdRp remains difficult and is not widely available. Therefore, we prepared a database of commercial small-molecule compounds and performed an in silico high-throughput virtual screening on the active site of the SARS-CoV-2 RdRp using ensemble docking. We identified a novel thioether-amide or guanidine-linker class of potential RdRp inhibitors and calculated favorable binding free energies of representative hits by molecular dynamics simulations coupled with Linear Interaction Energy calculations. This innovative procedure maximized the respective phase-space sampling and yielded non-covalent inhibitors representing small optimizable molecules that are synthetically readily accessible, commercially available as well as suitable for further biological evaluation and mode of action studies.
We have developed a new system, ProBiS-Dock, which can be used to determine the different types of protein binding sites for small ligands. The binding sites identified this way are then used to ...construct a new binding site database, the ProBiS-Dock Database, that allows for the ranking of binding sites according to their utility for drug development. The newly constructed database currently has more than 1.4 million binding sites and offers the possibility to investigate potential drug targets originating from different biological species. The interactive ProBiS-Dock Database, a web server and repository that consists of all small-molecule ligand binding sites in all of the protein structures in the Protein Data Bank, is freely available at http://probis-dock-database.insilab.org. The ProBiS-Dock Database will be regularly updated to keep pace with the growth of the Protein Data Bank, and our anticipation is that it will be useful in drug discovery.
We introduce a new algorithm MaxCliqueWeight for identifying a maximum weight clique in a weighted graph, and its variant MaxCliqueDynWeight with dynamically varying bounds. This algorithm uses an ...efficient branch-and-bound approach with a new weighted graph coloring algorithm that efficiently determines upper weight bounds for a maximum weighted clique in a graph. We evaluate our algorithm on random weighted graphs with node counts up to 10,000 and on standard DIMACS benchmark graphs used in a variety of research areas. Our findings reveal a remarkable improvement in computational speed when compared to existing algorithms, particularly evident in the case of high-density random graphs and DIMACS graphs, where our newly developed algorithm outperforms existing alternatives by several orders of magnitude. The newly developed algorithm and its variant are freely available to the broader research community at http://insilab.org/maxcliqueweight , paving the way for transformative applications in various research areas, including drug discovery.
Drug development is a lengthy and challenging process that can be accelerated at early stages by new mathematical approaches and modern computers. To address this important issue, we are developing ...new mathematical solutions for the detection and characterization of protein binding sites that are important for new drug development. In this review, we present algorithms based on graph theory combined with molecular dynamics simulations that we have developed for studying biological target proteins to provide important data for optimizing the early stages of new drug development. A particular focus is the development of new protein binding site prediction algorithms (ProBiS) and new web tools for modeling pharmaceutically interesting molecules—ProBiS Tools (algorithm, database, web server), which have evolved into a full-fledged graphical tool for studying proteins in the proteome. ProBiS differs from other structural algorithms in that it can align proteins with different folds without prior knowledge of the binding sites. It allows detection of similar binding sites and can predict molecular ligands of various types of pharmaceutical interest that could be advanced to drugs to treat a disease, based on the entire Protein Data Bank (PDB) and AlphaFold database, including proteins not yet in the PDB. All ProBiS Tools are freely available to the academic community at
http://insilab.org
and
https://probis.nih.gov
.
•We review the recent advances in binding site comparison approach.•We examine its use in protein function prediction.•We discuss its uses in pharmaceutical discovery.
While structural genomics ...resulted in thousands of new protein crystal structures, we still do not know the functions of most of these proteins. One reason for this shortcoming is their unique sequences or folds, which leaves them assigned as proteins of ‘unknown function’. Recent advances in and applications of cutting edge binding site comparison algorithms for binding site detection and function prediction have begun to shed light on this problem. Here, we review these algorithms and their use in function prediction and pharmaceutical discovery. Finding common binding sites in weakly related proteins may lead to the discovery of new protein functions and to novel ways of drug discovery.
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