Journal of Cheminformatics最新文献

Over the past ~ 25 years, chemoinformatics has evolved as a scientific discipline, with a strong foundation in pharmaceutical research and scientific roots that can be traced back to the late 1950s. It covers a wide methodological spectrum and is perhaps best positioned in the greater context of chemical information science. Herein, the chemoinformatics discipline is delineated, characteristic (and partly problematic) features are discussed, and a global view of the field is provided, emphasizing key developments.

The adverse outcome pathway (AOP) concept has gained attention as a way to explore the mechanism of chemical toxicity. In this study, quantitative structure–activity relationship (QSAR) models were developed to predict compound activity toward protein targets relevant to molecular initiating events (MIE) upstream of organ-specific toxicities, namely liver steatosis, cholestasis, nephrotoxicity, neural tube closure defects, and cognitive functional defects. Utilizing bioactivity data from the ChEMBL 33 database, various machine learning algorithms, chemical features and methods to assess prediction reliability were compared and applied to develop robust models to predict compound activity. The results demonstrate high predictive performance across multiple targets, with balanced accuracy exceeding 0.80 for the majority of models. Furthermore, stability checks confirmed the consistency of predictive performance across multiple training-test splits. The results obtained by using QSAR predictions to identify known markers of adversities highlighted the utility of the models for risk assessment and for prioritizing compounds for further experimental evaluation.

Scientific contribution

The work describes the development of QSAR models as tools for screening chemicals with potential systemic toxicity, thus contributing to resource savings and providing indications for further better-targeted testing. This study provides advances in the field of computational modeling of MIEs and information from AOP which is still relatively young and unexplored. The comprehensive modeling procedure is highly generalizable, and offers a robust framework for predicting a wide range of toxicological endpoints.

Molecular dynamics simulations serve as a prevalent approach for investigating the dynamic behaviour of proteins and protein–ligand complexes. Due to its versatility and speed, GROMACS stands out as a commonly utilized software platform for executing molecular dynamics simulations. However, its effective utilization requires substantial expertise in configuring, executing, and interpreting molecular dynamics trajectories. Existing automation tools are constrained in their capability to conduct simulations for large sets of compounds with minimal user intervention, or in their ability to distribute simulations across multiple servers. To address these challenges, we developed a Python-based tool that streamlines all phases of molecular dynamics simulations, encompassing preparation, execution, and analysis. This tool minimizes the required knowledge for users engaging in molecular dynamics simulations and can efficiently operate across multiple servers within a network or a cluster. Notably, the tool not only automates trajectory simulation but also facilitates the computation of free binding energies for protein–ligand complexes and generates interaction fingerprints across the trajectory. Our study demonstrated the applicability of this tool on several benchmark datasets. Additionally, we provided recommendations for end-users to effectively utilize the tool.

Scientific contribution

The developed tool, StreaMD, is applicable to different systems (proteins, ligands and their complexes including co-factors) and requires a little user knowledge to setup and run molecular dynamics simulations. Other features of StreaMD are seamless integration with calculation of MM-GBSA/PBSA binding free energies and protein-ligand interaction fingerprints, and running of simulations within distributed environments. All these will facilitate routine and massive molecular dynamics simulations.

This article highlights research from the last century that has provided the basis for the searching techniques that are used in present-day cheminformatics systems, and thus provides an acknowledgement of the contributions made by early pioneers in the field.

We introduce an advanced model for predicting protein–ligand interactions. Our approach combines the strengths of graph neural networks with physics-based scoring methods. Existing structure-based machine-learning models for protein–ligand binding prediction often fall short in practical virtual screening scenarios, hindered by the intricacies of binding poses, the chemical diversity of drug-like molecules, and the scarcity of crystallographic data for protein–ligand complexes. To overcome the limitations of existing machine learning-based prediction models, we propose a novel approach that fuses three independent neural network models. One classification model is designed to perform binary prediction of a given protein–ligand complex pose. The other two regression models are trained to predict the binding affinity and root-mean-square deviation of a ligand conformation from an input complex structure. We trained the model to account for both deviations in experimental and predicted binding affinities and pose prediction uncertainties. By effectively integrating the outputs of the triplet neural networks with a physics-based scoring function, our model showed a significantly improved performance in hit identification. The benchmark results with three independent decoy sets demonstrate that our model outperformed existing models in forward screening. Our model achieved top 1% enrichment factors of 32.7 and 23.1 with the CASF2016 and DUD-E benchmark sets, respectively. The benchmark results using the LIT-PCBA set further confirmed its higher average enrichment factors, emphasizing the model’s efficiency and generalizability. The model’s efficiency was further validated by identifying 23 active compounds from 63 candidates in experimental screening for autotaxin inhibitors, demonstrating its practical applicability in hit discovery.

Scientific contribution

Our work introduces a novel training strategy for a protein–ligand binding affinity prediction model by integrating the outputs of three independent sub-models and utilizing expertly crafted decoy sets. The model showcases exceptional performance across multiple benchmarks. The high enrichment factors in the LIT-PCBA benchmark demonstrate its potential to accelerate hit discovery.

State‑of‑the‑art medical studies proved that predicting CYP450 enzyme inhibitors is beneficial in the early stage of drug discovery. However, accurate machine learning-based (ML) in silico methods for predicting CYP450 inhibitors remains challenging. Here, we introduce GTransCYPs, an improved graph neural network (GNN) with a transformer mechanism for predicting CYP450 inhibitors. This model significantly enhances the discrimination between inhibitors and non-inhibitors for five major CYP450 isozymes: 1A2, 2C9, 2C19, 2D6, and 3A4. GTransCYPs learns information patterns from molecular graphs by aggregating node and edge representations using a transformer. The GTransCYPs model utilizes transformer convolution layers to process features, followed by a global attention-pooling technique to synthesize the graph-level information. This information is then fed through successive linear layers for final output generation. Experimental results demonstrate that the GTransCYPs model achieved high performance, outperforming other state-of-the-art methods in CYP450 prediction.

Scientific contribution

The prediction of CYP450 inhibition via computational techniques utilizing biological information has emerged as a cost-effective and highly efficient approach. Here, we presented a deep learning (DL) architecture based on GNN with transformer mechanism and attention pooling (GTransCYPs) to predict CYP450 inhibitors. Four GTransCYPs of different pooling technique were tested on an experimental tasks on the CYP450 prediction problem for the first time. Graph transformer with attention pooling algorithm achieved the best performances. Comparative and ablation experiments provide evidence of the efficacy of our proposed method in predicting CYP450 inhibitors. The source code is publicly available at https://github.com/zonwoo/GTransCYPs.

The evaluation of compound-target interactions (CTIs) is at the heart of drug discovery efforts. Given the substantial time and monetary costs of classical experimental screening, significant efforts have been dedicated to develop deep learning-based models that can accurately predict CTIs. A comprehensive comparison of these models on a large, curated CTI dataset is, however, still lacking. Here, we perform an in-depth comparison of 12 state-of-the-art deep learning architectures that use different protein and compound representations. The models were selected for their reported performance and architectures. To reliably compare model performance, we curated over 300 thousand binding and non-binding CTIs and established several gold-standard datasets of varying size and information. Based on our findings, DeepConv-DTI consistently outperforms other models in CTI prediction performance across the majority of datasets. It achieves an MCC of 0.6 or higher for most of the datasets and is one of the fastest models in training and inference. These results indicate that utilizing convolutional-based windows as in DeepConv-DTI to traverse trainable embeddings is a highly effective approach for capturing informative protein features. We also observed that physicochemical embeddings of targets increased model performance. We therefore modified DeepConv-DTI to include normalized physicochemical properties, which resulted in the overall best performing model Phys-DeepConv-DTI. This work highlights how the systematic evaluation of input features of compounds and targets, as well as their corresponding neural network architectures, can serve as a roadmap for the future development of improved CTI models.

Scientific contribution

This work features comprehensive CTI datasets to allow for the objective comparison and benchmarking of CTI prediction algorithms. Based on this dataset, we gained insights into which embeddings of compounds and targets and which deep learning-based algorithms perform best, providing a blueprint for the future development of CTI algorithms. Using the insights gained from this screen, we provide a novel CTI algorithm with state-of-the-art performance.

A crucial mechanism for controlling the actions of proteins is allostery. Allosteric modulators have the potential to provide many benefits compared to orthosteric ligands, such as increased selectivity and saturability of their effect. The identification of new allosteric sites presents prospects for the creation of innovative medications and enhances our comprehension of fundamental biological mechanisms. Allosteric sites are increasingly found in different protein families through various techniques, such as machine learning applications, which opens up possibilities for creating completely novel medications with a diverse variety of chemical structures. Machine learning methods, such as PASSer, exhibit limited efficacy in accurately finding allosteric binding sites when relying solely on 3D structural information.

Scientific Contribution

Prior to conducting feature selection for allosteric binding site identification, integration of supporting amino-acid–based information to 3D structural knowledge is advantageous. This approach can enhance performance by ensuring accuracy and robustness. Therefore, we have developed an accurate and robust model called Multimodel Ensemble Feature Selection for Allosteric Site Identification (MEF-AlloSite) after collecting 9460 relevant and diverse features from the literature to characterise pockets. The model employs an accurate and robust multimodal feature selection technique for the small training set size of only 90 proteins to improve predictive performance. This state-of-the-art technique increased the performance in allosteric binding site identification by selecting promising features from 9460 features. Also, the relationship between selected features and allosteric binding sites enlightened the understanding of complex allostery for proteins by analysing selected features. MEF-AlloSite and state-of-the-art allosteric site identification methods such as PASSer2.0 and PASSerRank have been tested on three test cases 51 times with a different split of the training set. The Student’s t test and Cohen’s D value have been used to evaluate the average precision and ROC AUC score distribution. On three test cases, most of the p-values ((< 0.05)) and the majority of Cohen’s D values ((> 0.5)) showed that MEF-AlloSite’s 1–6% higher mean of average precision and ROC AUC than state-of-the-art allosteric site identification methods are statistically significant.