A community effort in SARS-CoV-2 drug discovery.

The COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against COVID-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors.

AI-Powered Virtual Screening of Large Compound Libraries Leads to the Discovery of Novel Inhibitors of Sirtuin-1.

The discovery of new scaffolds and chemotypes via high-throughput screening is tedious and resource intensive. Yet, there are millions of small molecules commercially available, rendering comprehensive in vitro tests intractable. We show how smart algorithms reduce large screening collections to target-specific sets of just a few hundred small molecules, allowing for a much faster and more cost-effective hit discovery process.

An interaction-based drug discovery screen explains known SARS-CoV-2 inhibitors and predicts new compound scaffolds.

The recent outbreak of the COVID-19 pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has shown the necessity for fast and broad drug discovery methods to enable us to react quickly to novel and highly infectious diseases. A well-known SARS-CoV-2 target is the viral main 3-chymotrypsin-like cysteine protease (M), known to control coronavirus replication, which is essential for the viral life cycle. Here, we applied an interaction-based drug repositioning algorithm on all protein-compound complexes available in the protein database (PDB) to identify M inhibitors and potential novel compound scaffolds against SARS-CoV-2.

Evaluation of Betulinic Acid Derivatives as PET Tracers for Hypoxia-Induced Carbonic Anhydrase IX (CA IX) Expression.

Non-invasive visualisation of the expression of hypoxia-related proteins, such as carbonic anhydrase IX (CA IX), by positron emission tomography (PET) could provide important information on the oxygenation status of tumours. Since betulinic acid derivatives bind specifically to CA IX the aim of the study was the development betulinic acid-based Ga-labelled PET tracers and to evaluate the hypoxia detecting properties in vitro and in vivo. The binding of betulinic acid (B-DOTA) and betulinyl-3-sulfamate (BS-DOTA) was assessed in two rat tumour cell lines (AT1 prostate and Walker-256 mammary carcinomas).

Structural binding site comparisons reveal Crizotinib as a novel LRRK2 inhibitor.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a frequent cause of autosomal dominant Parkinson's disease (PD) and have been associated with familial and sporadic PD. Reducing the kinase activity of LRRK2 is a promising therapeutic strategy since pathogenic mutations increase the kinase activity. Several small-molecule LRRK2 inhibitors are currently under investigation for the treatment of PD.

PLIP 2021: expanding the scope of the protein-ligand interaction profiler to DNA and RNA.

With the growth of protein structure data, the analysis of molecular interactions between ligands and their target molecules is gaining importance. PLIP, the protein-ligand interaction profiler, detects and visualises these interactions and provides data in formats suitable for further processing. PLIP has proven very successful in applications ranging from the characterisation of docking experiments to the assessment of novel ligand-protein complexes.

Repositioned Drugs for Chagas Disease Unveiled via Structure-Based Drug Repositioning.

Chagas disease, caused by the parasite , affects millions of people in South America. The current treatments are limited, have severe side effects, and are only partially effective. Drug repositioning, defined as finding new indications for already approved drugs, has the potential to provide new therapeutic options for Chagas.

The structural basis of the genetic code: amino acid recognition by aminoacyl-tRNA synthetases.

Storage and directed transfer of information is the key requirement for the development of life. Yet any information stored on our genes is useless without its correct interpretation. The genetic code defines the rule set to decode this information.

Computational Drug Repositioning for Chagas Disease Using Protein-Ligand Interaction Profiling.

Chagas disease, caused by (), affects nearly eight million people worldwide. There are currently only limited treatment options, which cause several side effects and have drug resistance. Thus, there is a great need for a novel, improved Chagas treatment.

Structure-based drug repositioning explains ibrutinib as VEGFR2 inhibitor.

Many drugs are promiscuous and bind to multiple targets. On the one hand, these targets may be linked to unwanted side effects, but on the other, they may achieve a combined desired effect (polypharmacology) or represent multiple diseases (drug repositioning). With the growth of 3D structures of drug-target complexes, it is today possible to study drug promiscuity at the structural level and to screen vast amounts of drug-target interactions to predict side effects, polypharmacological potential, and repositioning opportunities.

Extracellular Acidosis Modulates the Expression of Epithelial-Mesenchymal Transition (EMT) Markers and Adhesion of Epithelial and Tumor Cells.

Epithelial-to-mesenchymal transition (EMT) is an important process of tumor progression associated with increased metastatic potential. EMT can be activated by external triggers such as cytokines or metabolic parameters (e.g.

Backbone Brackets and Arginine Tweezers delineate Class I and Class II aminoacyl tRNA synthetases.

The origin of the machinery that realizes protein biosynthesis in all organisms is still unclear. One key component of this machinery are aminoacyl tRNA synthetases (aaRS), which ligate tRNAs to amino acids while consuming ATP. Sequence analyses revealed that these enzymes can be divided into two complementary classes.

From malaria to cancer: Computational drug repositioning of amodiaquine using PLIP interaction patterns.

Drug repositioning identifies new indications for known drugs. Here we report repositioning of the malaria drug amodiaquine as a potential anti-cancer agent. While most repositioning efforts emerge through serendipity, we have devised a computational approach, which exploits interaction patterns shared between compounds.

Inhibition of Carbonic Anhydrase IX by Ureidosulfonamide Inhibitor U104 Reduces Prostate Cancer Cell Growth, But Does Not Modulate Daunorubicin or Cisplatin Cytotoxicity.

Carbonic anhydrase (CA) IX has emerged as a promising target for cancer therapy. It is highly upregulated in hypoxic regions and mediates pH regulation critical for tumor cell survival as well as extracellular acidification of the tumor microenvironment, which promotes tumor aggressiveness via various mechanisms, such as augmenting metastatic potential. Therefore, the aim of this study was to analyze the complex interdependency between CA IX and the tumor microenvironment in prostate tumor cells with regard to potential therapeutic implications.

Pioneering topological methods for network-based drug-target prediction by exploiting a brain-network self-organization theory.

The bipartite network representation of the drug-target interactions (DTIs) in a biosystem enhances understanding of the drugs' multifaceted action modes, suggests therapeutic switching for approved drugs and unveils possible side effects. As experimental testing of DTIs is costly and time-consuming, computational predictors are of great aid. Here, for the first time, state-of-the-art DTI supervised predictors custom-made in network biology were compared-using standard and innovative validation frameworks-with unsupervised pure topological-based models designed for general-purpose link prediction in bipartite networks.

Discovery of Mycobacterium tuberculosis InhA Inhibitors by Binding Sites Comparison and Ligands Prediction.

Drug discovery is usually focused on a single protein target; in this process, existing compounds that bind to related proteins are often ignored. We describe ProBiS plugin, extension of our earlier ProBiS-ligands approach, which for a given protein structure allows prediction of its binding sites and, for each binding site, the ligands from similar binding sites in the Protein Data Bank. We developed a new database of precalculated binding site comparisons of about 290000 proteins to allow fast prediction of binding sites in existing proteins.

New HSP27 inhibitors efficiently suppress drug resistance development in cancer cells.

Drug resistance is an important open problem in cancer treatment. In recent years, the heat shock protein HSP27 (HSPB1) was identified as a key player driving resistance development. HSP27 is overexpressed in many cancer types and influences cellular processes such as apoptosis, DNA repair, recombination, and formation of metastases.

The chemical class of quinazoline compounds provides a core structure for the design of anticytomegaloviral kinase inhibitors.

HCMV is a member of the family Herpesviridae and represents a worldwide distributed pathogen with seropositivity rates in the adult population ranging between 40% and 90%. Notably, HCMV infection is a serious, sometimes life-threatening medical problem for newborns and immunosuppressed individuals, including transplant recipients and patients under antitumoral chemotherapy. Current standard therapy with valganciclovir has the disadvantage of inducing drug-resistant virus mutants and toxicity-related side effects.

The effects of timing of prophylaxis, type of anesthesia, and use of mechanical methods on outcome in major orthopedic surgery - subgroup analyses from 17,701 patients in the XAMOS study.

Purpose: Real-world data on the use of rivaroxaban in the perioperative period in patients undergoing major orthopedic surgery are limited. Subsets of data from the Phase IV, non-interventional XAMOS study were analyzed to explore the potential influence of timing of the first thrombo prophylactic dose, type of anesthesia, and concomitant mechanical prophylaxis on clinical outcomes in patients undergoing major orthopedic surgery in routine clinical practice.

Patients And Methods: In XAMOS, 8,778 patients received rivaroxaban (10 mg once daily) and 8,635 received standard-of-care (SOC) pharmacological prophylaxis (safety population).

Computational Drug Repositioning by Target Hopping: A Use Case in Chagas Disease.

Background: Drug repositioning aims to identify novel indications for existing drugs. One approach to repositioning exploits shared binding sites between the drug targets and other proteins. Here, we review the principle and algorithms of such target hopping and illustrate them in Chagas disease, an in Latin America widely spread, but neglected disease.

PLIP: fully automated protein-ligand interaction profiler.

The characterization of interactions in protein-ligand complexes is essential for research in structural bioinformatics, drug discovery and biology. However, comprehensive tools are not freely available to the research community. Here, we present the protein-ligand interaction profiler (PLIP), a novel web service for fully automated detection and visualization of relevant non-covalent protein-ligand contacts in 3D structures, freely available at projects.

XALIA: rationale and design of a non-interventional study of rivaroxaban compared with standard therapy for initial and long-term anticoagulation in deep vein thrombosis.

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism, poses a substantial clinical risk, and the incidence of these thrombotic-related diseases remains high. Anticoagulation aims to prevent thrombus extension and reduce the risk of recurrent events, particularly fatal pulmonary embolism. In EINSTEIN DVT, rivaroxaban was non-inferior to enoxaparin/vitamin K antagonists for the reduction of recurrent VTE, with a similar safety profile and a net clinical benefit.

Polypharmacology rescored: protein-ligand interaction profiles for remote binding site similarity assessment.

Detection of remote binding site similarity in proteins plays an important role for drug repositioning and off-target effect prediction. Various non-covalent interactions such as hydrogen bonds and van-der-Waals forces drive ligands' molecular recognition by binding sites in proteins. The increasing amount of available structures of protein-small molecule complexes enabled the development of comparative approaches.

Drug Promiscuity in PDB: Protein Binding Site Similarity Is Key.

Drug repositioning applies established drugs to new disease indications with increasing success. A pre-requisite for drug repurposing is drug promiscuity (polypharmacology) - a drug's ability to bind to several targets. There is a long standing debate on the reasons for drug promiscuity.