Knowledge-augmented Graph Machine Learning for Drug Discovery: A Survey from Precision to Interpretability

The integration of Artificial Intelligence (AI) into the field of drug discovery has been a growing area of interdisciplinary scientific research. However, conventional AI models are heavily limited in handling complex biomedical structures (such as 2D or 3D protein and molecule structures) and providing interpretations for outputs, which hinders their practical application. As of late, Graph Machine Learning (GML) has gained considerable attention for its exceptional ability to model graph-structured biomedical data and investigate their properties and functional relationships. Despite extensive efforts, GML methods still suffer from several deficiencies, such as the limited ability to handle supervision sparsity and provide interpretability in learning and inference processes, and their ineffectiveness in utilising relevant domain knowledge. In response, recent studies have proposed integrating external biomedical knowledge into the GML pipeline to realise more precise and interpretable drug discovery with limited training instances. However, a systematic definition for this burgeoning research direction is yet to be established. This survey presents a comprehensive overview of long-standing drug discovery principles, provides the foundational concepts and cutting-edge techniques for graph-structured data and knowledge databases, and formally summarises Knowledge-augmented Graph Machine Learning (KaGML) for drug discovery. A thorough review of related KaGML works, collected following a carefully designed search methodology, are organised into four categories following a novel-defined taxonomy. To facilitate research in this promptly emerging field, we also share collected practical resources that are valuable for intelligent drug discovery and provide an in-depth discussion of the potential avenues for future advancements

Identification of cellular factors that regulate Ty1 retrotransposition in S. cerevisiae

Les éléments transposables (ETs) sont des séquences d’ADN mobiles qui ont la propriété remarquable de se déplacer et se propager dans les génomes. Découverts dans les années 1940 chez le maïs, ils sont présents dans tous les génomes séquencés à ce jour. Bien que le nombre d’études décrivant leur rôle dans l’évolution, la fonction et la structure des génomes n’a cessé d’augmenter depuis, nous sommes encore loin de comprendre toute l’étendue de l’impact biologique des ETs sur les organismes. La distribution des ETs n'est pas aléatoire, phénomène dû en partie aux mécanismes qui orientent l’intégration vers des régions préférentielles du génome. C’est le cas du rétrotransposon Ty1 de la levure S. cerevisiae, qui s’intègre principalement dans une fenêtre d’une kilobase en amont des gènes transcrits par l’ARN polymérase III (Pol III). Cette spécificité résulte d’une interaction entre l’intégrase codée par l’élément et une sous-unité de la Pol III, AC40. En son absence, Ty1 cible préférentiellement les subtélomères, ce qui suggère l’existence d’autres facteurs régulant la sélectivité d’intégration du rétrotransposon. Ce travail a eu pour but d’identifier ces facteurs par deux approches complémentaires. D’une part, nous avons étudié le rôle des marques d’histones corrélant avec les insertions de Ty1 dans le choix du site d’intégration. D’autre part, nous avons recherché de nouveaux partenaires de l’intégrase de Ty1 par une approche protéomique à grande échelle. Si nos résultats n’ont pas permis d’identifier de nouveaux facteurs cellulaires impliqués dans la reconnaissance du site d’intégration de Ty1, ils ont élargi le répertoire des protéines de l’hôte qui régulent la rétrotransposition de Ty1. En effet, nous avons découvert que le variant d’histone H2A.Z et la protéine kinase CK2 répriment la rétrotransposition de Ty1. CK2 agit aux étapes transcriptionnelle et post-transcriptionnelle, interagit avec l’intégrase in vivo et la phosphoryle in vitro sur plusieurs résidus dans le domaine C-terminal, régulant probablement ainsi sa stabilité. Des expériences supplémentaires seront nécessaires pour confirmer cette hypothèse, découvrir par quel mécanisme CK2 régule Ty1, et comprendre le rôle de H2A.Z.Transposable elements (TEs) are mobile DNA sequences, with the extraordinary ability to jump and propagate in genomes. Discovered in the 1940s in maize, they are present in all sequenced genomes. Even if a large amount of data reveals their role in evolution, function and structure of genomes, we are still far from understanding every facet of their biological impact on organisms. TEs are not distributed randomly, partly due to mechanisms that target the integration to preferred genomic regions. This is the case for Ty1, a retrotransposon of S. cerevisiae, that targets a one-kilobase window upstream of RNA Polymerase III (Pol III)-transcribed genes. This specificity is due to an interaction between the element-encoded integrase and AC40, a subunit of Pol III. When this interaction is disrupted, Ty1 insertions are redistributed to subtelomeres, which suggests that other factors that regulate the integration selectivity of the retrotransposon exist. The aim of this work was to determine those factors by two complementary approaches. First, we studied the implication in this process of histone variants that correlate with Ty1 integration sites. Second, we identified new partners of Ty1 integrase by a proteomic screen. Our results did not lead us to identifying new cellular factors involved in the recognition of Ty1 integration site. They however widened the array of host proteins that regulate Ty1 retrotransposition. Indeed, we found that the histone variant H2A.Z and the protein kinase CK2 repress Ty1 retrotransposition. CK2 acts at transcriptional and post-transcriptional steps, interacts with the integrase in vivo and phosphorylates it in vitro on several residues in the C-terminal domain, probably thereby regulating its stability. Additional experiments will be required to confirm this hypothesis, to discover by which mechanisms CK2 regulates Ty1, and to understand the role of H2A.Z

Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia

Slow-channel congenital myasthenic syndromes (SCCMSs) are rare genetic diseases caused by mutations in muscle nicotinic acetylcholine receptor (nAChR) subunits. Most of the known SCCMS-associated mutations localize at the transmembrane region near the ion pore. Only two SCCMS point mutations are at the extracellular domains near the acetylcholine binding site, α1(G153S) being one of them. In this work, a combination of molecular dynamics, targeted mutagenesis, fluorescent Ca2+ imaging and patch-clamp electrophysiology has been applied to G153S mutant muscle nAChR to investigate the role of hydrogen bonds formed by Ser 153 with C-loop residues near the acetylcholine-binding site. Introduction of L199T mutation to the C-loop in the vicinity of Ser 153 changed hydrogen bonds distribution, decreased acetylcholine potency (EC50 2607 vs. 146 nM) of the double mutant and decay kinetics of acetylcholine-evoked cytoplasmic Ca2+ rise (τ 14.2 ± 0.3 vs. 34.0 ± 0.4 s). These results shed light on molecular mechanisms of nAChR activation-desensitization and on the involvement of such mechanisms in channelopathy genesis

A proteomic screen of Ty1 integrase partners identifies the protein kinase CK2 as a regulator of Ty1 retrotransposition

Abstract Background Transposable elements are ubiquitous and play a fundamental role in shaping genomes during evolution. Since excessive transposition can be mutagenic, mechanisms exist in the cells to keep these mobile elements under control. Although many cellular factors regulating the mobility of the retrovirus-like transposon Ty1 in Saccharomyces cerevisiae have been identified in genetic screens, only very few of them interact physically with Ty1 integrase (IN). Results Here, we perform a proteomic screen to establish Ty1 IN interactome. Among the 265 potential interacting partners, we focus our study on the conserved CK2 kinase. We confirm the interaction between IN and CK2, demonstrate that IN is a substrate of CK2 in vitro and identify the modified residues. We find that Ty1 IN is phosphorylated in vivo and that these modifications are dependent in part on CK2. No significant change in Ty1 retromobility could be observed when we introduce phospho-ablative mutations that prevent IN phosphorylation by CK2 in vitro . However, the absence of CK2 holoenzyme results in a strong stimulation of Ty1 retrotransposition, characterized by an increase in Ty1 mRNA and protein levels and a high accumulation of cDNA. Conclusion Our study shows that Ty1 IN is phosphorylated, as observed for retroviral INs and highlights an important role of CK2 in the regulation of Ty1 retrotransposition. In addition, the proteomic approach enabled the identification of many new Ty1 IN interacting partners, whose potential role in the control of Ty1 mobility will be interesting to study