Databases of ligand-binding pockets and protein-ligand interactions.

Many research groups and institutions have created a variety of databases curating experimental and predicted data related to protein-ligand binding. The landscape of available databases is dynamic, with new databases emerging and established databases becoming defunct. Here, we review the current state of databases that contain binding pockets and protein-ligand binding interactions. We have compiled a list of such databases, fifty-three of which are currently available for use. We discuss variation in how binding pockets are defined and summarize pocket-finding methods. We organize the fifty-three databases into subgroups based on goals and contents, and describe standard use cases. We also illustrate that pockets within the same protein are characterized differently across different databases. Finally, we assess critical issues of sustainability, accessibility and redundancy.

Heterogeneous network approaches to protein pathway prediction.

Understanding protein-protein interactions (PPIs) and the pathways they comprise is essential for comprehending cellular functions and their links to specific phenotypes. Despite the prevalence of molecular data generated by high-throughput sequencing technologies, a significant gap remains in translating this data into functional information regarding the series of interactions that underlie phenotypic differences. In this review, we present an in-depth analysis of heterogeneous network methodologies for modeling protein pathways, highlighting the critical role of integrating multifaceted biological data. It outlines the process of constructing these networks, from data representation to machine learning-driven predictions and evaluations. The work underscores the potential of heterogeneous networks in capturing the complexity of proteomic interactions, thereby offering enhanced accuracy in pathway prediction. This approach not only deepens our understanding of cellular processes but also opens up new possibilities in disease treatment and drug discovery by leveraging the predictive power of comprehensive proteomic data analysis.

Computational Approaches to Drug Repurposing: Methods, Challenges, and Opportunities.

Drug repurposing refers to the inference of therapeutic relationships between a clinical indication and existing compounds. As an emerging paradigm in drug development, drug repurposing enables more efficient treatment of rare diseases, stratified patient populations, and urgent threats to public health. However, prioritizing well-suited drug candidates from among a nearly infinite number of repurposing options continues to represent a significant challenge in drug development. Over the past decade, advances in genomic profiling, database curation, and machine learning techniques have enabled more accurate identification of drug repurposing candidates for subsequent clinical evaluation. This review outlines the major methodologic classes that these approaches comprise, which rely on (a) protein structure, (b) genomic signatures, (c) biological networks, and (d) real-world clinical data. We propose that realizing the full impact of drug repurposing methodologies requires a multidisciplinary understanding of each method's advantages and limitations with respect to clinical practice.

Elucidating the semantics-topology trade-off for knowledge inference-based pharmacological discovery.

Leveraging AI for synthesizing the deluge of biomedical knowledge has great potential for pharmacological discovery with applications including developing new therapeutics for untreated diseases and repurposing drugs as emergent pandemic treatments. Creating knowledge graph representations of interacting drugs, diseases, genes, and proteins enables discovery via embedding-based ML approaches and link prediction. Previously, it has been shown that these predictive methods are susceptible to biases from network structure, namely that they are driven not by discovering nuanced biological understanding of mechanisms, but based on high-degree hub nodes. In this work, we study the confounding effect of network topology on biological relation semantics by creating an experimental pipeline of knowledge graph semantic and topological perturbations. We show that the drop in drug repurposing performance from ablating meaningful semantics increases by 21% and 38% when mitigating topological bias in two networks. We demonstrate that new methods for representing knowledge and inferring new knowledge must be developed for making use of biomedical semantics for pharmacological innovation, and we suggest fruitful avenues for their development.

Leveraging large-scale biobank EHRs to enhance pharmacogenetics of cardiometabolic disease medications.

Electronic health records (EHRs) coupled with large-scale biobanks offer great promises to unravel the genetic underpinnings of treatment efficacy. However, medication-induced biomarker trajectories stemming from such records remain poorly studied. Here, we extract clinical and medication prescription data from EHRs and conduct GWAS and rare variant burden tests in the UK Biobank (discovery) and the All of Us program (replication) on ten cardiometabolic drug response outcomes including lipid response to statins, HbA1c response to metformin and blood pressure response to antihypertensives (N = 740-26,669). Our findings at genome-wide significance level recover previously reported pharmacogenetic signals and also include novel associations for lipid response to statins (N = 26,669) near LDLR and ZNF800. Importantly, these associations are treatment-specific and not associated with biomarker progression in medication-naive individuals. Furthermore, we demonstrate that individuals with higher genetically determined low-density and total cholesterol baseline levels experience increased absolute, albeit lower relative biomarker reduction following statin treatment. In summary, we systematically investigated the common and rare pharmacogenetic contribution to cardiometabolic drug response phenotypes in over 50,000 UK Biobank and All of Us participants with EHR and identified clinically relevant genetic predictors for improved personalized treatment strategies.

Prospector Heads: Generalized Feature Attribution for Large Models & Data.

Feature attribution, the ability to localize regions of the input data that are relevant for classification, is an important capability for ML models in scientific and biomedical domains. Current methods for feature attribution, which rely on "explaining" the predictions of end-to-end classifiers, suffer from imprecise feature localization and are inadequate for use with small sample sizes and high-dimensional datasets due to computational challenges. We introduce prospector heads, an efficient and interpretable alternative to explanation-based attribution methods that can be applied to any encoder and any data modality. Prospector heads generalize across modalities through experiments on sequences (text), images (pathology), and graphs (protein structures), outperforming baseline attribution methods by up to 26.3 points in mean localization AUPRC. We also demonstrate how prospector heads enable improved interpretation and discovery of class-specific patterns in input data. Through their high performance, flexibility, and generalizability, prospectors provide a framework for improving trust and transparency for ML models in complex domains.

Which Social Media Platforms Provide the Most Informative Data for Monitoring the Opioid Crisis?

Background and Aims: Social media can provide real-time insight into trends in substance use, addiction, and recovery. Prior studies have leveraged data from platforms such as Reddit and X (formerly Twitter), but evolving policies around data access have threatened their usability in opioid overdose surveillance systems. Here, we evaluate the potential of a broad set of platforms to detect emerging trends in the opioid crisis. Design: We identified 72 online platforms with a substantial global user base or prior citations in opioid-related research. We evaluated each platform's fit with our definition of social media, size of North American user base, and volume of opioid-related discourse. We created a shortlist of 11 platforms that met our criteria. We documented basic characteristics, volume and nature of opioid discussion, official policies regulating drug-related discussion, and data accessibility of shortlisted platforms. Setting: USA and Canada. Measurements: We quantified the volume of opioid discussion by number of platform-specific Google search hits for opioid terms. We captured informal language by including slang generated using a large language model. We report the number of opioid-related hits and proportion of opioid-related hits to hits for common nouns. Findings: We found that TikTok, YouTube, and Facebook have the most potential for use in opioid-related surveillance. TikTok and Facebook have the highest relative amount of drug-related discussions. Language on TikTok was predominantly informal. Many platforms offer data access tools for research, but changing company policies and user norms create instability. The demographics of users varies substantially across platforms. Conclusions: Social media data sources hold promise for detecting trends in opioid use, but researchers must consider the utility, accessibility, and stability of data on each platform. A strategy mixing several platforms may be required to cover all demographics suffering in the epidemic.