PLIP, the protein–ligand interaction profiler, analyses molecular interactions in protein structures. PLIP detects eight types of non-covalent interactions. Initially focused on small-molecule, DNA, and RNA interactions to a protein, the current release incorporates protein–protein interactions. We document the usefulness of this feature by comparing PLIP interactions of the cancer drug venetoclax with the native protein–protein interaction of Bcl-2 and BAX. PLIP reveals how the drug mimics the native interaction, as there is critical overlap in the interaction profiles. PLIP is available as a web server, source code with containers, and Jupyter notebook. The PLIP web server is online at https://plip-tool.biotec.tu-dresden.de.

Chagas disease, caused by the parasite Trypanosoma cruzi, 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. In this work, we conducted a structure-based drug repositioning approach with over 130,000 3D protein structures to identify drugs that bind therapeutic Chagas targets and thus represent potential new Chagas treatments. The screening yielded over 500 molecules as hits, out of which 38 drugs were prioritized following a rigorous filtering process. About half of the latter were already known to have trypanocidal activity, while the others are novel to Chagas disease. Three of the new drug candidates—ciprofloxacin, naproxen, and folic acid—showed a growth inhibitory activity in the micromolar range when tested ex vivo on T. cruzi trypomastigotes, validating the prediction. We show that our drug repositioning approach is able to pinpoint relevant drug candidates at a fraction of the time and cost of a conventional screening. Furthermore, our results demonstrate the power and potential of structure-based drug repositioning in the context of neglected tropical diseases where the pharmaceutical industry has little financial interest in the development of new drugs.

For optimal pancreatic cancer treatment, early and accurate diagnosis is vital. Blood-derived biomarkers and genetic predispositions can contribute to early diagnosis, but they often have limited accuracy or applicability. Here, we seek to exploit the synergy between them by combining the biomarker CA19-9 with RNA-based variants. We use deep sequencing and deep learning to improve differentiating pancreatic cancer and chronic pancreatitis. We obtained samples of nucleated cells found in peripheral blood from 268 patients suffering from resectable, non-resectable pancreatic cancer, and chronic pancreatitis. We sequenced RNA with high coverage and obtained millions of variants. The high-quality variants served as input together with CA19-9 values to deep learning models. Our model achieved an area under the curve (AUC) of 96% in differentiating resectable cancer from pancreatitis using a test cohort. Moreover, we identified variants to estimate survival in resectable cancer. We show that the blood transcriptome harbours variants, which can substantially improve noninvasive clinical diagnosis.

Promiscuity denotes the ability of ligands and targets to specifically interact with multiple binding partners. Despite negative aspects like side effects, promiscuity is receiving increasing attention in drug discovery as it can enhance drug efficacy and provides a molecular basis for drug repositioning. The three-dimensional structure of ligand-target complexes delivers exclusive insights into the molecular mechanisms of promiscuity and structure-based methods enable the identification of promiscuous interactions. With the recent breakthrough in protein structure prediction, novel possibilities open up to reveal unknown connections in ligand-target interaction networks. This review highlights the significance of structure in the identification and characterization of promiscuity and evaluates the potential of protein structure prediction to advance our knowledge of drug-target interaction networks. It discusses the definition and relevance of promiscuity in drug discovery and explores different approaches to detecting promiscuous ligands and targets. Examination of structural data is essential for understanding and quantifying promiscuity. The recent advancements in structure prediction have resulted in an abundance of targets that are well-suited for structure-based methods like docking. In silico approaches may eventually completely transform our understanding of drug-target networks by complementing the millions of predicted protein structures with billions of predicted drug-target interactions.

Promiscuity of drugs and targets plays an important role in drug-target prediction, ranging from the explanation of side effects to their exploitation in drug repositioning. A specific form of promiscuity concerns drugs, which interfere with protein-protein interactions. With the rising importance of such drugs in drug discovery and with the large-scale availability of structural data, the question arises on the structural basis of this form of promiscuity and the commonalities of the underlying protein-ligand (PLI) and protein-protein interactions (PPI). The authors applied the protein-ligand interaction profiler, PLIP, to experimental and predicted structures and characterize drugs in clinical trials, which target PPI. PPIs generally involve more non-covalent interactions than PLI with overlapping interaction patterns and key binding site residues. In contrast to experimental structures, predicted structures fall short in accurately capturing interaction details at the interface. Taken together, our analysis shows that PPIs and PLIs have sufficient commonalities to merit future work into computational screenings for drugs targeting PPIs. It will be key to further improve structure prediction, specifically for binding site details.