embryoTox: Using Graph-Based Signatures to Predict the Teratogenicity of Small Molecules.

Teratogenic drugs can lead to extreme fetal malformation and consequently critically influence the fetus's health, yet the teratogenic risks associated with most approved drugs are unknown. Here, we propose a novel predictive tool, embryoTox, which utilizes a graph-based signature representation of the chemical structure of a small molecule to predict and classify molecules likely to be safe during pregnancy. embryoTox was trained and validated using in vitro bioactivity data of over 700 small molecules with characterized teratogenicity effects. Our final model achieved an area under the receiver operating characteristic curve (AUC) of up to 0.96 on 10-fold cross-validation and 0.82 on nonredundant blind tests, outperforming alternative approaches. We believe that our predictive tool will provide a practical resource for optimizing screening libraries to determine effective and safe molecules to use during pregnancy. To provide a simple and integrated platform to rapidly screen for potential safe molecules and their risk factors, we made embryoTox freely available online at https://biosig.lab.uq.edu.au/embryotox/.

cardioToxCSM: A Web Server for Predicting Cardiotoxicity of Small Molecules.

The design of novel, safe, and effective drugs to treat human diseases is a challenging venture, with toxicity being one of the main sources of attrition at later stages of development. Failure due to toxicity incurs a significant increase in costs and time to market, with multiple drugs being withdrawn from the market due to their adverse effects. Cardiotoxicity, for instance, was responsible for the failure of drugs such as fenspiride, propoxyphene, and valdecoxib. While significant effort has been dedicated to mitigate this issue by developing computational approaches that aim to identify molecules likely to be toxic, including quantitative structure-activity relationship models and machine learning methods, current approaches present limited performance and interpretability. To overcome these, we propose a new web-based computational method, cardioToxCSM, which can predict six types of cardiac toxicity outcomes, including arrhythmia, cardiac failure, heart block, hERG toxicity, hypertension, and myocardial infarction, efficiently and accurately. cardioToxCSM was developed using the concept of graph-based signatures, molecular descriptors, toxicophore matchings, and molecular fingerprints, leveraging explainable machine learning, and was validated internally via different cross validation schemes and externally via low-redundancy blind sets. The models presented robust performances with areas under ROC curves of up to 0.898 on 5-fold cross-validation, consistent with metrics on blind tests. Additionally, our models provide interpretation of the predictions by identifying whether substructures that are commonly enriched in toxic compounds were present. We believe cardioToxCSM will provide valuable insight into the potential cardiotoxicity of small molecules early on drug screening efforts. The method is made freely available as a web server at https://biosig.lab.uq.edu.au/cardiotoxcsm.

piscesCSM: prediction of anticancer synergistic drug combinations.

While drug combination therapies are of great importance, particularly in cancer treatment, identifying novel synergistic drug combinations has been a challenging venture. Computational methods have emerged in this context as a promising tool for prioritizing drug combinations for further evaluation, though they have presented limited performance, utility, and interpretability. Here, we propose a novel predictive tool, piscesCSM, that leverages graph-based representations to model small molecule chemical structures to accurately predict drug combinations with favourable anticancer synergistic effects against one or multiple cancer cell lines. Leveraging these insights, we developed a general supervised machine learning model to guide the prediction of anticancer synergistic drug combinations in over 30 cell lines. It achieved an area under the receiver operating characteristic curve (AUROC) of up to 0.89 on independent non-redundant blind tests, outperforming state-of-the-art approaches on both large-scale oncology screening data and an independent test set generated by AstraZeneca (with more than a 16% improvement in predictive accuracy). Moreover, by exploring the interpretability of our approach, we found that simple physicochemical properties and graph-based signatures are predictive of chemotherapy synergism. To provide a simple and integrated platform to rapidly screen potential candidate pairs with favourable synergistic anticancer effects, we made piscesCSM freely available online at https://biosig.lab.uq.edu.au/piscescsm/ as a web server and API. We believe that our predictive tool will provide a valuable resource for optimizing and augmenting combinatorial screening libraries to identify effective and safe synergistic anticancer drug combinations. SCIENTIFIC CONTRIBUTION: This work proposes piscesCSM, a machine-learning-based framework that relies on well-established graph-based representations of small molecules to identify and provide better predictive accuracy of syngenetic drug combinations. Our model, piscesCSM, shows that combining physiochemical properties with graph-based signatures can outperform current architectures on classification prediction tasks. Furthermore, implementing our tool as a web server offers a user-friendly platform for researchers to screen for potential synergistic drug combinations with favorable anticancer effects against one or multiple cancer cell lines.

Understanding and predicting the functional consequences of missense mutations in BRCA1 and BRCA2.

BRCA1 and BRCA2 are tumour suppressor genes that play a critical role in maintaining genomic stability via the DNA repair mechanism. DNA repair defects caused by BRCA1 and BRCA2 missense variants increase the risk of developing breast and ovarian cancers. Accurate identification of these variants becomes clinically relevant, as means to guide personalized patient management and early detection. Next-generation sequencing efforts have significantly increased data availability but also the discovery of variants of uncertain significance that need interpretation. Experimental approaches used to measure the molecular consequences of these variants, however, are usually costly and time-consuming. Therefore, computational tools have emerged as faster alternatives for assisting in the interpretation of the clinical significance of newly discovered variants. To better understand and predict variant pathogenicity in BRCA1 and BRCA2, various machine learning algorithms have been proposed, however presented limited performance. Here we present BRCA1 and BRCA2 gene-specific models and a generic model for quantifying the functional impacts of single-point missense variants in these genes. Across tenfold cross-validation, our final models achieved a Matthew's Correlation Coefficient (MCC) of up to 0.98 and comparable performance of up to 0.89 across independent, non-redundant blind tests, outperforming alternative approaches. We believe our predictive tool will be a valuable resource for providing insights into understanding and interpreting the functional consequences of missense variants in these genes and as a tool for guiding the interpretation of newly discovered variants and prioritizing mutations for experimental validation.