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Compound-protein interactions (CPIs) are critical in drug discovery for identifying therapeutic targets, drug side effects, and repurposing existing drugs. Machine learning (ML) algorithms have emerged as powerful tools for CPI prediction, offering notable advantages in cost-effectiveness and efficiency. This review provides an overview of recent advances in both structure-based and non-structure-based CPI prediction ML models, highlighting their performance and achievements. It also offers insights into CPI prediction-related datasets and evaluation benchmarks. Lastly, the article presents a comprehensive assessment of the current landscape of CPI prediction, elucidating the challenges faced and outlining emerging trends to advance the field.

A new species of Dayongaspidae, Dayongaspis colubra sp. nov., is described from the Telychian (Llandovery, Silurian) Xiushan Formation at Maoyanhe Town, Zhangjiajie, Hunan Province, China. The new species is distinguished from the type species D. hunanensis by its larger-sized headshield, tiny and dense granular tubercles, and triangular-shaped inner cornual processes. Additionally, it reveals more galeaspid plesiomorphic characters than D. hunanensis, such as the inverted splayed posterior supraorbital canals (soc2) and the paired endolymphatic openings on the headshields. This new finding represents the first fossil record of galeaspids in the Xiushan Formation, thereby enriching the diversity of galeaspids. Furthermore, it extends the Wentang Vertebrate Assemblage upwards into the lower part of Xiushan Formation, indicating a broader stratigraphic range than previously assumed. [ABSTRACT FROM AUTHOR]

Ensuring drug safety in the early stages of drug development is crucial to avoid costly failures in subsequent phases. However, the economic burden associated with detecting drug off-targets and potential side effects through in vitro safety screening and animal testing is substantial. Drug off-target interactions, along with the adverse drug reactions they induce, are significant factors affecting drug safety. To assess the liability of candidate drugs, we developed an artificial intelligence model for the precise prediction of compound off-target interactions, leveraging multi-task graph neural networks. The outcomes of off-target predictions can serve as representations for compounds, enabling the differentiation of drugs under various ATC codes and the classification of compound toxicity. Furthermore, the predicted off-target profiles are employed in adverse drug reaction (ADR) enrichment analysis, facilitating the inference of potential ADRs for a drug. Using the withdrawn drug Pergolide as an example, we elucidate the mechanisms underlying ADRs at the target level, contributing to the exploration of the potential clinical relevance of newly predicted off-target interactions. Overall, our work facilitates the early assessment of compound safety/toxicity based on off-target identification, deduces potential ADRs of drugs, and ultimately promotes the secure development of drugs. An advanced framework for drug safety assessment, encompassing precise drug off-target profile prediction and its utilization in ATC classification, toxicity prediction, and ADR enrichment analysis. [Display omitted] [ABSTRACT FROM AUTHOR]

Accurate prediction of molecular properties is fundamental in drug discovery and development, providing crucial guidance for effective drug design. A critical factor in achieving accurate molecular property prediction lies in the appropriate representation of molecular structures. Presently, prevalent deep learning–based molecular representations rely on 2D structure information as the primary molecular representation, often overlooking essential three-dimensional (3D) conformational information due to the inherent limitations of 2D structures in conveying atomic spatial relationships. In this study, we propose employing the Gram matrix as a condensed representation of 3D molecular structures and for efficient pretraining objectives. Subsequently, we leverage this matrix to construct a novel molecular representation model, Pre-GTM, which inherently encapsulates 3D information. The model accurately predicts the 3D structure of a molecule by estimating the Gram matrix. Our findings demonstrate that Pre-GTM model outperforms the baseline Graphormer model and other pretrained models in the QM9 and MoleculeNet quantitative property prediction task. The integration of the Gram matrix as a condensed representation of 3D molecular structure, incorporated into the Pre-GTM model, opens up promising avenues for its potential application across various domains of molecular research, including drug design, materials science, and chemical engineering. [ABSTRACT FROM AUTHOR]

Drought is a frequent global phenomenon. Solar-induced chlorophyll fluorescence (SIF), an electromagnetic signal, has been proven to be an efficient tool for monitoring and assessing gross primary productivity (GPP) and drought. To address the issue of the sparse resolution of satellite-based SIF, researchers have developed different downscaling algorithms. Recently, the most frequently used SIF products had a spatial resolution of 0.05 degrees. However, these spatial resolution SIF data are not conducive to regional agricultural drought monitoring. In this study, we utilized the global 'OCO-2' solar-induced fluorescence (GOSIF) products along with normalized difference vegetation index (NDVI) and land surface temperature (LST) products. With the powerful advantages offered by Google Earth Engine (GEE), we could conveniently acquire the necessary data. Additionally, employing the random forest (RF) method, we successfully acquired downscaled SIF data at an enhanced spatial resolution of 1 km. Using those downscaled SIF results with 1 km resolution, an SIF anomaly index was established and calculated to monitor drought. Results showed that the RF-based downscaled SIF result followed the same trend as the GOSIF value. Subsequently, correlation coefficients between SIF and GPP were calculated. The downscaled SIF demonstrated a higher correlation with GPP from MODIS compared to 0.05-degree GOSIF, with coefficients of 0.74 and 0.68 in May 2018, respectively. Moreover, the SIF anomaly index showed positive correlations with crop yield; the correlation coefficients were 0.93 for wheat and 0.89 for maize. The drought index had a negative correlation with areas affected by drought, with a correlation coefficient of −0.58. Finally, the SIF anomaly index was used to monitor drought from 2001 to 2020 in Henan Province. The 1 km SIF results obtained through the RF-based downscaled method were deemed reliable, thereby establishing the suitability of the SIF anomaly index for drought monitoring at a regional scale. [ABSTRACT FROM AUTHOR]

Enhancing cancer treatment efficacy remains a significant challenge in human health. Immunotherapy has witnessed considerable success in recent years as a treatment for tumors. However, due to the heterogeneity of diseases, only a fraction of patients exhibit a positive response to immune checkpoint inhibitor (ICI) therapy. Various single-gene-based biomarkers and tumor mutational burden (TMB) have been proposed for predicting clinical responses to ICI; however, their predictive ability is limited. We propose the utilization of the Text Graph Convolutional Network (GCN) method to comprehensively assess the impact of multiple genes, aiming to improve the predictive capability for ICI response. We developed TG468, a Text GCN model framing drug response prediction as a text classification task. By combining natural language processing (NLP) and graph neural network techniques, TG468 effectively handles sparse and high-dimensional exome sequencing data. As a result, TG468 can distinguish survival time for patients who received ICI therapy and outperforms single gene biomarkers, TMB and some classical machine learning models. Additionally, TG468's prediction results facilitate the identification of immune status differences among specific patient types in the Cancer Genome Atlas dataset, providing a rationale for the model's predictions. Our approach represents a pioneering use of a GCN model to analyze exome data in patients undergoing ICI therapy and offers inspiration for future research using NLP technology to analyze exome sequencing data. [ABSTRACT FROM AUTHOR]

Kinase inhibitors are crucial in cancer treatment, but drug resistance and side effects hinder the development of effective drugs. To address these challenges, it is essential to analyze the polypharmacology of kinase inhibitor and identify compound with high selectivity profile. This study presents KinomeMETA, a framework for profiling the activity of small molecule kinase inhibitors across a panel of 661 kinases. By training a meta-learner based on a graph neural network and fine-tuning it to create kinase-specific learners, KinomeMETA outperforms benchmark multi-task models and other kinase profiling models. It provides higher accuracy for understudied kinases with limited known data and broader coverage of kinase types, including important mutant kinases. Case studies on the discovery of new scaffold inhibitors for membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase and selective inhibitors for fibroblast growth factor receptors demonstrate the role of KinomeMETA in virtual screening and kinome-wide activity profiling. Overall, KinomeMETA has the potential to accelerate kinase drug discovery by more effectively exploring the kinase polypharmacology landscape. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to assess the effects of bladder filling during cervical cancer radiotherapy on target volume and organs at risk (OARs) dose based on daily computed tomography (daily‐CT) images and provide bladder‐volume‐based dose prediction models. Methods: Nineteen patients (475 daily‐CTs) comprised the study group, and five patients comprised the validation set (25 daily‐CTs). Target volumes and OARs were delineated on daily‐CT images and the treatment plan was recalculated accordingly. The deviation from the planning bladder volume (DVB), the correlation between DVB and clinical (CTV)/planning (PTV) target volume in terms of prescribed dose coverage, and the relationship of small bowel volume and bladder dose with the ratio of bladder volume (RVB) were analyzed. Results: In all cases, the prescribed dose coverage in the CTV was >95% when DVB was <200 cm3, whereas that in the PTV was >95% when RVB was <160%. The ratio of bladder V45 Gy to the planning bladder V45 Gy (RBV45) exhibited a negative linear relationship with RVB (RBV45 = −0.18*RVB + 120.8; R2 = 0.80). Moreover, the ratio of small bowel volume to planning small bowel volume (RVS) exhibited a negative linear relationship with RVB (RVS = −1.06*RVB +217.59; R2 = 0.41). The validation set results showed that the linear model predicted well the effects of bladder volume changes on target volume coverage and bladder dose. Conclusions: This study assessed dosimetry and volume effects of bladder filling on target and OARs based on daily‐CT images. We established a quantitative relationship between these parameters, providing dose prediction models for cervical cancer radiotherapy. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) conformations of a small molecule profoundly affect its binding to the target of interest, the resulting biological effects, and its disposition in living organisms, but it is challenging to accurately characterize the conformational ensemble experimentally. Here, we proposed an autoregressive torsion angle prediction model Tora3D for molecular 3D conformer generation. Rather than directly predicting the conformations in an end-to-end way, Tora3D predicts a set of torsion angles of rotatable bonds by an interpretable autoregressive method and reconstructs the 3D conformations from them, which keeps structural validity during reconstruction. Another advancement of our method over other conformational generation methods is the ability to use energy to guide the conformation generation. In addition, we propose a new message-passing mechanism that applies the Transformer to the graph to solve the difficulty of remote message passing. Tora3D shows superior performance to prior computational models in the trade-off between accuracy and efficiency, and ensures conformational validity, accuracy, and diversity in an interpretable way. Overall, Tora3D can be used for the quick generation of diverse molecular conformations and 3D-based molecular representation, contributing to a wide range of downstream drug design tasks. [ABSTRACT FROM AUTHOR]