Promiscuity in drug discovery on the verge of the structural revolution: recent advances and future chances.

Introduction: 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.

Decomposing compounds enables reconstruction of interaction fingerprints for structure-based drug screening.

Background: Structure-based drug repositioning has emerged as a promising alternative to conventional drug development. Regardless of the many success stories reported over the past years and the novel breakthroughs on the AI-based system AlphaFold for structure prediction, the availability of structural data for protein-drug complexes remains very limited. Whereas the chemical libraries contain millions of drug compounds, the vast majority of them do not have structures to crystallized targets,and it is, therefore, impossible to characterize their binding to targets from a structural view.

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.

Deep Learning Improves Pancreatic Cancer Diagnosis Using RNA-Based Variants.

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.

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.

Toward an Understanding of Pan-Assay Interference Compounds and Promiscuity: A Structural Perspective on Binding Modes.

Pan-assay interference compounds (PAINS) are promiscuous compound classes that produce false positive hits in high-throughput screenings. Yet, the mechanisms of PAINS activity are poorly understood. Although PAINS are often associated with protein reactivity, several recent studies have shown that they also mediate noncovalent interactions.

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.

SLAMF receptors negatively regulate B cell receptor signaling in chronic lymphocytic leukemia via recruitment of prohibitin-2.

We identified a subset of Chronic Lymphocytic Leukemia (CLL) patients with high Signaling Lymphocytic Activation Molecule Family (SLAMF) receptor-related signaling that showed an indolent clinical course. Since SLAMF receptors play a role in NK cell biology, we reasoned that these receptors may impact NK cell-mediated CLL immunity. Indeed, our experiments showed significantly decreased degranulation capacity of primary NK cells from CLL patients expressing low levels of SLAMF1 and SLAMF7.

Drug repositioning or target repositioning: A structural perspective of drug-target-indication relationship for available repurposed drugs.

Drug repositioning aims to find new indications for existing drugs in order to reduce drug development cost and time. Currently,there are numerous stories of successful drug repositioning that have been reported and many repurposed drugs are already available on the market. Although drug repositioning is often a product of serendipity, repositioning opportunities can be uncovered systematically.

An improved high cell density cultivation-iHCDC-strategy for leucine auxotrophic K12 ER2507.

Fed-batch processes are commonly used tools in high cell density cultivation of . However, the setup of a fed-batch process can be challenging, especially when working with genetically modified strains. This work deals with the design of a specific strategy for the leucine auxotrophic strain K12 ER2507 that is of interest for arabinose-inducible gene expression systems due to its mutation.