Large Language Model-Based Natural Language Encoding Could Be All You Need for Drug Biomedical Association Prediction.

Analyzing drug-related interactions in the field of biomedicine has been a critical aspect of drug discovery and development. While various artificial intelligence (AI)-based tools have been proposed to analyze drug biomedical associations (DBAs), their feature encoding did not adequately account for crucial biomedical functions and semantic concepts, thereby still hindering their progress. Since the advent of ChatGPT by OpenAI in 2022, large language models (LLMs) have demonstrated rapid growth and significant success across various applications. Herein, LEDAP was introduced, which uniquely leveraged LLM-based biotext feature encoding for predicting drug-disease associations, drug-drug interactions, and drug-side effect associations. Benefiting from the large-scale knowledgebase pre-training, LLMs had great potential in drug development analysis owing to their holistic understanding of natural language and human topics. LEDAP illustrated its notable competitiveness in comparison with other popular DBA analysis tools. Specifically, even in simple conjunction with classical machine learning methods, LLM-based feature representations consistently enabled satisfactory performance across diverse DBA tasks like binary classification, multiclass classification, and regression. Our findings underpinned the considerable potential of LLMs in drug development research, indicating a catalyst for further progress in related fields.

MOINER: A Novel Multiomics Early Integration Framework for Biomedical Classification and Biomarker Discovery.

In the context of precision medicine, multiomics data integration provides a comprehensive understanding of underlying biological processes and is critical for disease diagnosis and biomarker discovery. One commonly used integration method is early integration through concatenation of multiple dimensionally reduced omics matrices due to its simplicity and ease of implementation. However, this approach is seriously limited by information loss and lack of latent feature interaction. Herein, a novel multiomics early integration framework (MOINER) based on information enhancement and image representation learning is thus presented to address the challenges. MOINER employs the self-attention mechanism to capture the intrinsic correlations of omics-features, which make it significantly outperform the existing state-of-the-art methods for multiomics data integration. Moreover, visualizing the attention embedding and identifying potential biomarkers offer interpretable insights into the prediction results. All source codes and model for MOINER are freely available https://github.com/idrblab/MOINER.

Strategy for Identifying a Robust Metabolomic Signature Reveals the Altered Lipid Metabolism in Pituitary Adenoma.

Despite the well-established connection between systematic metabolic abnormalities and the pathophysiology of pituitary adenoma (PA), current metabolomic studies have reported an extremely limited number of metabolites associated with PA. Moreover, there was very little consistency in the identified metabolite signatures, resulting in a lack of robust metabolic biomarkers for the diagnosis and treatment of PA. Herein, we performed a global untargeted plasma metabolomic profiling on PA and identified a highly robust metabolomic signature based on a strategy. Specifically, this strategy is unique in (1) integrating repeated random sampling and a consensus evaluation-based feature selection algorithm and (2) evaluating the consistency of metabolomic signatures among different sample groups. This strategy demonstrated superior robustness and stronger discriminative ability compared with that of other feature selection methods including Student's t-test, partial least-squares-discriminant analysis, support vector machine recursive feature elimination, and random forest recursive feature elimination. More importantly, a highly robust metabolomic signature comprising 45 PA-specific differential metabolites was identified. Moreover, metabolite set enrichment analysis of these potential metabolic biomarkers revealed altered lipid metabolism in PA. In conclusion, our findings contribute to a better understanding of the metabolic changes in PA and may have implications for the development of diagnostic and therapeutic approaches targeting lipid metabolism in PA. We believe that the proposed strategy serves as a valuable tool for screening robust, discriminating metabolic features in the field of metabolomics.

AnnoPRO: a strategy for protein function annotation based on multi-scale protein representation and a hybrid deep learning of dual-path encoding.

Protein function annotation has been one of the longstanding issues in biological sciences, and various computational methods have been developed. However, the existing methods suffer from a serious long-tail problem, with a large number of GO families containing few annotated proteins. Herein, an innovative strategy named AnnoPRO was therefore constructed by enabling sequence-based multi-scale protein representation, dual-path protein encoding using pre-training, and function annotation by long short-term memory-based decoding. A variety of case studies based on different benchmarks were conducted, which confirmed the superior performance of AnnoPRO among available methods. Source code and models have been made freely available at: https://github.com/idrblab/AnnoPRO and https://zenodo.org/records/10012272.

Is fragment-based graph a better graph-based molecular representation for drug design? A comparison study of graph-based models.

Graph Neural Networks (GNNs) have gained significant traction in various sectors of AI-driven drug design. Over recent years, the integration of fragmentation concepts into GNNs has emerged as a potent strategy to augment the efficacy of molecular generative models. Nonetheless, challenges such as symmetry breaking and potential misrepresentation of intricate cycles and undefined functional groups raise questions about the superiority of fragment-based graph representation over traditional methods. In our research, we undertook a rigorous evaluation, contrasting the predictive prowess of eight models-developed using deep learning algorithms-across 12 benchmark datasets that span a range of properties. These models encompass established methods like GCN, AttentiveFP, and D-MPNN, as well as innovative fragment-based representation techniques. Our results indicate that fragment-based methodologies, notably PharmHGT, significantly improve model performance and interpretability, particularly in scenarios characterized by limited data availability. However, in situations with extensive training, fragment-based molecular graph representations may not necessarily eclipse traditional methods. In summation, we posit that the integration of fragmentation, as an avant-garde technique in drug design, harbors considerable promise for the future of AI-enhanced drug design.

TheMarker: a comprehensive database of therapeutic biomarkers.

Distinct from the traditional diagnostic/prognostic biomarker (adopted as the indicator of disease state/process), the therapeutic biomarker (ThMAR) has emerged to be very crucial in the clinical development and clinical practice of all therapies. There are five types of ThMAR that have been found to play indispensable roles in various stages of drug discovery, such as: Pharmacodynamic Biomarker essential for guaranteeing the pharmacological effects of a therapy, Safety Biomarker critical for assessing the extent or likelihood of therapy-induced toxicity, Monitoring Biomarker indispensable for guiding clinical management by serially measuring patients' status, Predictive Biomarker crucial for maximizing the clinical outcome of a therapy for specific individuals, and Surrogate Endpoint fundamental for accelerating the approval of a therapy. However, these data of ThMARs has not been comprehensively described by any of the existing databases. Herein, a database, named 'TheMarker', was therefore constructed to (a) systematically offer all five types of ThMAR used at different stages of drug development, (b) comprehensively describe ThMAR information for the largest number of drugs among available databases, (c) extensively cover the widest disease classes by not just focusing on anticancer therapies. These data in TheMarker are expected to have great implication and significant impact on drug discovery and clinical practice, and it is freely accessible without any login requirement at: https://idrblab.org/themarker.

CellSTAR: a comprehensive resource for single-cell transcriptomic annotation.

Large-scale studies of single-cell sequencing and biological experiments have successfully revealed expression patterns that distinguish different cell types in tissues, emphasizing the importance of studying cellular heterogeneity and accurately annotating cell types. Analysis of gene expression profiles in these experiments provides two essential types of data for cell type annotation: annotated references and canonical markers. In this study, the first comprehensive database of single-cell transcriptomic annotation resource (CellSTAR) was thus developed. It is unique in (a) offering the comprehensive expertly annotated reference data for annotating hundreds of cell types for the first time and (b) enabling the collective consideration of reference data and marker genes by incorporating tens of thousands of markers. Given its unique features, CellSTAR is expected to attract broad research interests from the technological innovations in single-cell transcriptomics, the studies of cellular heterogeneity & dynamics, and so on. It is now publicly accessible without any login requirement at: https://idrblab.org/cellstar.

Decoding Drug Response with Structurized Gridding Map-based Cell Representation.

A thorough understanding of cell-line drug response mechanisms is crucial for drug development, repurposing, and resistance reversal. While targeted anticancer therapies have shown promise, not all cancers have well-established biomarkers to stratify drug response. Single-gene associations only explain a small fraction of the observed drug sensitivity, so a more comprehensive method is needed. However, while deep learning models have shown promise in predicting drug response in cell lines, they still face significant challenges when it comes to their application in clinical applications. Therefore, this study proposed a new strategy called DD-Response for cell-line drug response prediction. First, a limitation of narrow modeling horizons was overcome to expand the model training domain by integrating multiple datasets through source-specific label binarization. Second, a modified representation based on a two-dimensional structurized gridding map (SGM) was developed for cell lines & drugs, avoiding feature correlation neglect and potential information loss. Third, a dual-branch, multi-channel convolutional neural network-based model for pairwise response prediction was constructed, enabling accurate outcomes and improved exploration of underlying mechanisms. As a result, the DD-Response demonstrated superior performance, captured cell-line characteristic variations, and provided insights into key factors impacting cell-line drug response. In addition, DD-Response exhibited scalability in predicting clinical patient responses to drug therapy. Overall, because of DD-response's excellent ability to predict drug response and capture key molecules behind them, DD-response is expected to greatly facilitate drug discovery, repurposing, resistance reversal, and therapeutic optimization.

A task-specific encoding algorithm for RNAs and RNA-associated interactions based on convolutional autoencoder.

RNAs play essential roles in diverse physiological and pathological processes by interacting with other molecules (RNA/protein/compound), and various computational methods are available for identifying these interactions. However, the encoding features provided by existing methods are limited and the existing tools does not offer an effective way to integrate the interacting partners. In this study, a task-specific encoding algorithm for RNAs and RNA-associated interactions was therefore developed. This new algorithm was unique in (a) realizing comprehensive RNA feature encoding by introducing a great many of novel features and (b) enabling task-specific integration of interacting partners using convolutional autoencoder-directed feature embedding. Compared with existing methods/tools, this novel algorithm demonstrated superior performances in diverse benchmark testing studies. This algorithm together with its source code could be readily accessed by all user at: https://idrblab.org/corain/ and https://github.com/idrblab/corain/.

A Transformer-Based Ensemble Framework for the Prediction of Protein-Protein Interaction Sites.

The identification of protein-protein interaction (PPI) sites is essential in the research of protein function and the discovery of new drugs. So far, a variety of computational tools based on machine learning have been developed to accelerate the identification of PPI sites. However, existing methods suffer from the low predictive accuracy or the limited scope of application. Specifically, some methods learned only global or local sequential features, leading to low predictive accuracy, while others achieved improved performance by extracting residue interactions from structures but were limited in their application scope for the serious dependence on precise structure information. There is an urgent need to develop a method that integrates comprehensive information to realize proteome-wide accurate profiling of PPI sites. Herein, a novel ensemble framework for PPI sites prediction, EnsemPPIS, was therefore proposed based on transformer and gated convolutional networks. EnsemPPIS can effectively capture not only global and local patterns but also residue interactions. Specifically, EnsemPPIS was unique in (a) extracting residue interactions from protein sequences with transformer and (b) further integrating global and local sequential features with the ensemble learning strategy. Compared with various existing methods, EnsemPPIS exhibited either superior performance or broader applicability on multiple PPI sites prediction tasks. Moreover, pattern analysis based on the interpretability of EnsemPPIS demonstrated that EnsemPPIS was fully capable of learning residue interactions within the local structure of PPI sites using only sequence information. The web server of EnsemPPIS is freely available at http://idrblab.org/ensemppis.

A novel strategy for designing the magic shotguns for distantly related target pairs.

Due to its promising capacity in improving drug efficacy, polypharmacology has emerged to be a new theme in the drug discovery of complex disease. In the process of novel multi-target drugs (MTDs) discovery, in silico strategies come to be quite essential for the advantage of high throughput and low cost. However, current researchers mostly aim at typical closely related target pairs. Because of the intricate pathogenesis networks of complex diseases, many distantly related targets are found to play crucial role in synergistic treatment. Therefore, an innovational method to develop drugs which could simultaneously target distantly related target pairs is of utmost importance. At the same time, reducing the false discovery rate in the design of MTDs remains to be the daunting technological difficulty. In this research, effective small molecule clustering in the positive dataset, together with a putative negative dataset generation strategy, was adopted in the process of model constructions. Through comprehensive assessment on 10 target pairs with hierarchical similarity-levels, the proposed strategy turned out to reduce the false discovery rate successfully. Constructed model types with much smaller numbers of inhibitor molecules gained considerable yields and showed better false-hit controllability than before. To further evaluate the generalization ability, an in-depth assessment of high-throughput virtual screening on ChEMBL database was conducted. As a result, this novel strategy could hierarchically improve the enrichment factors for each target pair (especially for those distantly related/unrelated target pairs), corresponding to target pair similarity-levels.

DRESIS: the first comprehensive landscape of drug resistance information.

Widespread drug resistance has become the key issue in global healthcare. Extensive efforts have been made to reveal not only diverse diseases experiencing drug resistance, but also the six distinct types of molecular mechanisms underlying this resistance. A database that describes a comprehensive list of diseases with drug resistance (not just cancers/infections) and all types of resistance mechanisms is now urgently needed. However, no such database has been available to date. In this study, a comprehensive database describing drug resistance information named 'DRESIS' was therefore developed. It was introduced to (i) systematically provide, for the first time, all existing types of molecular mechanisms underlying drug resistance, (ii) extensively cover the widest range of diseases among all existing databases and (iii) explicitly describe the clinically/experimentally verified resistance data for the largest number of drugs. Since drug resistance has become an ever-increasing clinical issue, DRESIS is expected to have great implications for future new drug discovery and clinical treatment optimization. It is now publicly accessible without any login requirement at: https://idrblab.org/dresis/.

DrugMAP: molecular atlas and pharma-information of all drugs.

The efficacy and safety of drugs are widely known to be determined by their interactions with multiple molecules of pharmacological importance, and it is therefore essential to systematically depict the molecular atlas and pharma-information of studied drugs. However, our understanding of such information is neither comprehensive nor precise, which necessitates the construction of a new database providing a network containing a large number of drugs and their interacting molecules. Here, a new database describing the molecular atlas and pharma-information of drugs (DrugMAP) was therefore constructed. It provides a comprehensive list of interacting molecules for >30 000 drugs/drug candidates, gives the differential expression patterns for >5000 interacting molecules among different disease sites, ADME (absorption, distribution, metabolism and excretion)-relevant organs and physiological tissues, and weaves a comprehensive and precise network containing >200 000 interactions among drugs and molecules. With the great efforts made to clarify the complex mechanism underlying drug pharmacokinetics and pharmacodynamics and rapidly emerging interests in artificial intelligence (AI)-based network analyses, DrugMAP is expected to become an indispensable supplement to existing databases to facilitate drug discovery. It is now fully and freely accessible at: https://idrblab.org/drugmap/.

Application of Machine Learning in Spatial Proteomics.

Spatial proteomics is an interdisciplinary field that investigates the localization and dynamics of proteins, and it has gained extensive attention in recent years, especially the subcellular proteomics. Numerous evidence indicate that the subcellular localization of proteins is associated with various cellular processes and disease progression. Mass spectrometry (MS)-based and imaging-based experimental approaches have been developed to acquire large-scale spatial proteomic data. To allow the reliable analysis of increasingly complex spatial proteomics data, machine learning (ML) methods have been widely used in both MS-based and imaging-based spatial proteomic data analysis pipelines. Here, we comprehensively survey the applications of ML in spatial proteomics from following aspects: (1) data resources for spatial proteome are comprehensively introduced; (2) the roles of different ML algorithms in data analysis pipelines are elaborated; (3) successful applications of spatial proteomics and several analytical tools integrating ML methods are presented; (4) challenges existing in modern ML-based spatial proteomics studies are discussed. This review provides guidelines for researchers seeking to apply ML methods to analyze spatial proteomic data and can facilitate insightful understanding of cell biology as well as the future research in medical and drug discovery communities.

ncRNAInter: a novel strategy based on graph neural network to discover interactions between lncRNA and miRNA.

In recent years, many studies have illustrated the significant role that non-coding RNA (ncRNA) plays in biological activities, in which lncRNA, miRNA and especially their interactions have been proved to affect many biological processes. Some in silico methods have been proposed and applied to identify novel lncRNA-miRNA interactions (LMIs), but there are still imperfections in their RNA representation and information extraction approaches, which imply there is still room for further improving their performances. Meanwhile, only a few of them are accessible at present, which limits their practical applications. The construction of a new tool for LMI prediction is thus imperative for the better understanding of their relevant biological mechanisms. This study proposed a novel method, ncRNAInter, for LMI prediction. A comprehensive strategy for RNA representation and an optimized deep learning algorithm of graph neural network were utilized in this study. ncRNAInter was robust and showed better performance of 26.7% higher Matthews correlation coefficient than existing reputable methods for human LMI prediction. In addition, ncRNAInter proved its universal applicability in dealing with LMIs from various species and successfully identified novel LMIs associated with various diseases, which further verified its effectiveness and usability. All source code and datasets are freely available at https://github.com/idrblab/ncRNAInter.

REGLIV: Molecular regulation data of diverse living systems facilitating current multiomics research.

Multiomics is a powerful technique in molecular biology that facilitates the identification of new associations among different molecules (genes, proteins & metabolites). It has attracted tremendous research interest from the scientists worldwide and has led to an explosive number of published studies. Most of these studies are based on the regulation data provided in available databases. Therefore, it is essential to have molecular regulation data that are strictly validated in the living systems of various cell lines and in vivo models. However, no database has been developed yet to provide comprehensive molecular regulation information validated by living systems. Herein, a new database, Molecular Regulation Data of Living System Facilitating Multiomics Study (REGLIV) is introduced to describe various types of molecular regulation tested by the living systems. (1) A total of 2996 regulations describe the changes in 1109 metabolites triggered by alterations in 284 genes or proteins, and (2) 1179 regulations describe the variations in 926 proteins induced by 125 endogenous metabolites. Overall, REGLIV is unique in (a) providing the molecular regulation of a clearly defined regulatory direction other than simple correlation, (b) focusing on molecular regulations that are validated in a living system not simply in an in vitro test, and (c) describing the disease/tissue/species specific property underlying each regulation. Therefore, REGLIV has important implications for the future practice of not only multiomics, but also other fields relevant to molecular regulation. REGLIV is freely accessible at: https://idrblab.org/regliv/.

Biological activities of drug inactive ingredients.

In a drug formulation (DFM), the major components by mass are not Active Pharmaceutical Ingredient (API) but rather Drug Inactive Ingredients (DIGs). DIGs can reach much higher concentrations than that achieved by API, which raises great concerns about their clinical toxicities. Therefore, the biological activities of DIG on physiologically relevant target are widely demanded by both clinical investigation and pharmaceutical industry. However, such activity data are not available in any existing pharmaceutical knowledge base, and their potentials in predicting the DIG-target interaction have not been evaluated yet. In this study, the comprehensive assessment and analysis on the biological activities of DIGs were therefore conducted. First, the largest number of DIGs and DFMs were systematically curated and confirmed based on all drugs approved by US Food and Drug Administration. Second, comprehensive activities for both DIGs and DFMs were provided for the first time to pharmaceutical community. Third, the biological targets of each DIG and formulation were fully referenced to available databases that described their pharmaceutical/biological characteristics. Finally, a variety of popular artificial intelligence techniques were used to assess the predictive potential of DIGs' activity data, which was the first evaluation on the possibility to predict DIG's activity. As the activities of DIGs are critical for current pharmaceutical studies, this work is expected to have significant implications for the future practice of drug discovery and precision medicine.

GIMICA: host genetic and immune factors shaping human microbiota.

Besides the environmental factors having tremendous impacts on the composition of microbial community, the host factors have recently gained extensive attentions on their roles in shaping human microbiota. There are two major types of host factors: host genetic factors (HGFs) and host immune factors (HIFs). These factors of each type are essential for defining the chemical and physical landscapes inhabited by microbiota, and the collective consideration of both types have great implication to serve comprehensive health management. However, no database was available to provide the comprehensive factors of both types. Herein, a database entitled 'Host Genetic and Immune Factors Shaping Human Microbiota (GIMICA)' was constructed. Based on the 4257 microbes confirmed to inhabit nine sites of human body, 2851 HGFs (1368 single nucleotide polymorphisms (SNPs), 186 copy number variations (CNVs), and 1297 non-coding ribonucleic acids (RNAs)) modulating the expression of 370 microbes were collected, and 549 HIFs (126 lymphocytes and phagocytes, 387 immune proteins, and 36 immune pathways) regulating the abundance of 455 microbes were also provided. All in all, GIMICA enabled the collective consideration not only between different types of host factor but also between the host and environmental ones, which is freely accessible without login requirement at: https://idrblab.org/gimica/.

INTEDE: interactome of drug-metabolizing enzymes.

Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major interaction types in an interactome: microbiome-DME interaction (MICBIO), xenobiotics-DME interaction (XEOTIC) and host protein-DME interaction (HOSPPI). The interaction data of each type are essential for drug metabolism, and the collective consideration of multiple types has implication for the future practice of precision medicine. However, no database was designed to systematically provide the data of all types of DME interactions. Here, a database of the Interactome of Drug-Metabolizing Enzymes (INTEDE) was therefore constructed to offer these interaction data. First, 1047 unique DMEs (448 host and 599 microbial) were confirmed, for the first time, using their metabolizing drugs. Second, for these newly confirmed DMEs, all types of their interactions (3359 MICBIOs between 225 microbial species and 185 DMEs; 47 778 XEOTICs between 4150 xenobiotics and 501 DMEs; 7849 HOSPPIs between 565 human proteins and 566 DMEs) were comprehensively collected and then provided, which enabled the crosstalk analysis among multiple types. Because of the huge amount of accumulated data, the INTEDE made it possible to generalize key features for revealing disease etiology and optimizing clinical treatment. INTEDE is freely accessible at: https://idrblab.org/intede/.

MMEASE: Online meta-analysis of metabolomic data by enhanced metabolite annotation, marker selection and enrichment analysis.

Large-scale and long-term metabolomic studies have attracted widespread attention in the biomedical studies yet remain challenging despite recent technique progresses. In particular, the ineffective way of experiment integration and limited capacity in metabolite annotation are known issues. Herein, we constructed an online tool MMEASE enabling the integration of multiple analytical experiments with an enhanced metabolite annotation and enrichment analysis (https://idrblab.org/mmease/). MMEASE was unique in capable of (1) integrating multiple analytical blocks; (2) providing enriched annotation for >330 thousands of metabolites; (3) conducting enrichment analysis using various categories/sub-categories. All in all, MMEASE aimed at supplying a comprehensive service for large-scale and long-term metabolomics, which might provide valuable guidance to current biomedical studies. SIGNIFICANCE: To facilitate the studies of large-scale and long-term metabolomic analysis, MMEASE was developed to (1) achieve the online integration of multiple datasets from different analytical experiments, (2) provide the most diverse strategies for marker discovery, enabling performance assessment and (3) significantly amplify metabolite annotation and subsequent enrichment analysis. MMEASE aimed at supplying a comprehensive service for long-term and large-scale metabolomics, which might provide valuable guidance to current biomedical studies.