Biology subjects

Adasme, M. F.

Publications and source records attributed to Adasme, M. F..

3 recordsLinked to original sources

bioRxiv2026

Chemical Probes in Scientific Literature: Expanding and Validating Target-Disease Evidence

Chemical probes are indispensable tools for validating therapeutic hypotheses, yet their broader impact on early-stage drug discovery remains unquantified. To our knowledge, this study represents the first systematic, large-scale investigation of the chemical probe literature. By screening over 18 million articles using a high-quality dictionary of 561 chemical probes, we identified 20,000 articles mentioning a chemical probe which resulted in 5,558 unique target-disease (T-D) associations. Our analysis yields four principal findings that redefine the utility of these chemicals: First, we show that chemical probe evidence typically precedes the appearance of structured data in major knowledge bases by 1-7 years, providing a crucial lead time for target prioritisation. Second, we identified 353 T-D pairs (6.4%) with no prior evidence in the Open Targets Platform, highlighting the approachs discovery potential. Third, the application of strict novelty filters uncovered 135 new high-confidence associations between targets and diseases, revealing distinct opportunities for therapeutic repurposing in non-oncological, rare autoimmune diseases, and diseases without effective therapies due to complex biology or high treatment resistance. Finally, we demonstrate that chemical probes are essential for strengthening evidence, providing functional validation for associations previously supported only by weaker, correlative data such as RNA expression or animal models. Collectively, these findings illustrate that chemical probes catalyse early therapeutic discovery, emphasising the importance of cataloguing existing probes and identifying new ones.

bioinformatics↗

bioRxiv2019

Drug repositoning 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, numerous successful stories of drug repositioning have been reported and many drugs are already available on the market. Although many of those cases are products of serendipitous findings, repositioning opportunities can be uncovered systematically by following either a disease-centric approach, as a result of a close relation between an old and new indication, a target-centric one, which links a known target and its established drug to a new indication, or a drug-centric approach, which connects a known drug to a new target and its associated indication. The three approaches differ in their complexity, potential, and limits, and most important the necessary starting information and computational power. Which one is predominant in current drug repositioning and what does this imply for future developments? To address these questions, we systematically evaluated over 100 drugs, 200 targets structures and over 300 indications from the Drug Repositioning Database. Each of the analysed cases has been classified based on one of the three repositioning approaches, showing that the majority, more than 60%, falls within the disease-centric definition, around 30% within the target-centric, and only less than 10% within the drug-centric. We therefore concluded that so far repositioning has mainly been disease and target repositioning and not, as drug repositioning, as expected by definition. We discuss the reasons and suggest directions to exploit the full potential of techniques useful for drug-centric in order to sustain future rationale repositioning pipelines.

bioinformatics↗

bioRxiv2019

Structure-based drug repositioning reveals 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. Here, we pursue such an approach to identify drugs inactivating B-cells, whose dysregulation can function as a driver of autoimmune diseases. Screening over 500 kinases, we identified 22, whose knock out impeded the activation of B-cells. Among these 22 is the gene KDR, whose gene product VEGFR2 is a prominent cancer target with anti-VEGFR2 drugs on the market for over a decade. The main result of this paper is that structure-based drug repositioning for the identified kinase targets identified the cancer drug ibrutinib as micromolar VEGFR2 inhibitor with a very high therapeutic index in B-cell inactivation. These findings prove that ibrutinib is not only acting on the Brutons tyrosine kinase BTK, against which it was designed. Instead, it may be a polypharmacological drug, which additionally targets angiogenesis via inhibition of VEGFR2. Therefore ibrutinib carries potential to treat other VEGFR2 associated disease. Structure-based drug repositioning explains ibrutinibs anti VEGFR2 action through a specific pattern of interactions shared between BTK and VEGFR2. Overall, structure-based drug repositioning was able to predict these findings at a fraction of the time and cost of a conventional screen.

bioinformatics↗