Molecular Informatics最新文献

Drug development is a long and costly process, often limited by the toxicity and adverse drug reactions (ADRs) caused by drug candidates. Even on the market, some drugs can cause strong ADRs that can vary depending on an individual polymorphism. The development of Genome-wide association studies (GWAS) allowed the discovery of genetic variants of interest that may cause these effects. In this study, the objective was to investigate a deep learning approach to predict genetic variations potentially related to ADRs. We used single nucleotide polymorphisms (SNPs) information from dbSNP to create a network based on ADR-drug-target-mutations and extracted matrixes of interaction to build deep Neural Networks (DNN) models. Considering only information about mutations known to impact drug efficacy and drug safety from PharmGKB and drug adverse reactions based on the MedDRA System Organ Classes (SOCs), these DNN models reached a balanced accuracy of 0.61 in average. Including molecular fingerprints representing structural features of the drugs did not improve the performance of the models. To our knowledge, this is the first model that exploits DNN to predict ADR-drug-target-mutations. Although some improvements are suggested, these models can be of interest to analyze multiple compounds over all of the genes and polymorphisms information accessible and thus pave the way in precision medicine.

Virtual screening (VS) is one of the well-established approaches in drug discovery which speeds up the search for a bioactive molecule and, reduces costs and efforts associated with experiments. VS helps to narrow down the search space of chemical space and allows selecting fewer and more probable candidate compounds for experimental testing. Docking calculations are one of the commonly used and highly appreciated structure-based drug discovery methods. Databases for chemical structures of small molecules have been growing rapidly. However, at the moment virtual screening of large libraries via docking is not very common. In this work, we aim to accelerate docking studies by predicting docking scores without explicitly performing docking calculations. We experimented with an attention based long short-term memory (LSTM) neural network for an efficient prediction of docking scores as well as other machine learning models such as XGBoost. By using docking scores of a small number of ligands we trained our models and predicted docking scores of a few million molecules. Specifically, we tested our approaches on 11 datasets that were produced from in-house drug discovery studies. On average, by training models using only 7000 molecules we predicted docking scores of approximately 3.8 million molecules with R² (coefficient of determination) of 0.77 and Spearman rank correlation coefficient of 0.85. We designed the system with ease of use in mind. All the user needs to provide is a csv file containing SMILES and their respective docking scores, the system then outputs a model that the user can use for the prediction of docking score for a new molecule.

Pregnant females may use medications to manage health problems that develop during pregnancy or that they had prior to pregnancy. However, using medications during pregnancy has a potential risk to the fetus. Assessing the fetotoxicity of drugs is essential to ensure safe treatments, but the current process is challenged by ethical issues, time, and cost. Therefore, the need for in silico models to efficiently assess the fetotoxicity of drugs has recently emerged. Previous studies have proposed successful machine learning models for fetotoxicity prediction and even suggest molecular substructures that are possibly associated with fetotoxicity risks or protective effects. However, the interpretation of the decisions of the models on fetotoxicity prediction for each drug is still insufficient. This study constructed machine learning-based models that can predict the fetotoxicity of drugs while providing explanations for the decisions. For this, permutation feature importance was used to identify the general features that the model made significant in predicting the fetotoxicity of drugs. In addition, features associated with fetotoxicity for each drug were analyzed using the attention mechanism. The predictive performance of all the constructed models was significantly high (AUROC: 0.854-0.974, AUPR: 0.890-0.975). Furthermore, we conducted literature reviews on the predicted important features and found that they were highly associated with fetotoxicity. We expect that our model will benefit fetotoxicity research by providing an evaluation of fetotoxicity risks for drugs or drug candidates, along with an interpretation of that prediction.

Protein kinases are crucial cellular enzymes that facilitate the transfer of phosphates from adenosine triphosphate (ATP) to their substrates, thereby regulating numerous cellular activities. Dysfunctional kinase activity often leads to oncogenic conditions. Chosen by using structural similarity to 5UG9, we selected 79 crystal structures from the PDB and based on the position of the phenylalanine side chain in the DFG motif, we classified these 79 crystal structures into 5 group clusters. Our approach applies our kinematic flexibility analysis (KFA) to explore the flexibility of kinases in various activity states and examine the impact of the activation loop on kinase structure. KFA enables the rapid decomposition of macromolecules into different flexibility regions, allowing comprehensive analysis of conformational structures. The results reveal that the activation loop of kinases acts as a "lock" that stabilizes the active conformation of kinases by rigidifying the adjacent α-helices. Furthermore, we investigate specific kinase mutations, such as the L858R mutation commonly associated with non-small cell lung cancer, which induces increased flexibility in active-state kinases. In addition, through analyzing the hydrogen bond pattern, we examine the substructure of kinases in different states. Notably, active-state kinases exhibit a higher occurrence of α-helices compared to inactive-state kinases. This study contributes to the understanding of biomolecular conformation at a level relevant to drug development.

Antibiotic-resistant strains are an emerging threat to public health. The usage of antimicrobial peptides (AMPs) is one of the promising approaches to solve this problem. For the development of new AMPs, it is necessary to have reliable prediction methods. Recently, deep learning approaches have been used to predict AMP. In this paper, we want to compare simple and complex methods for these purposes. We used the BERT transformer to create sequence embeddings and the multilayer perceptron (MLP) and light attention (LA) approaches for classification. One of them reached about 80 % accuracy and specificity in benchmark testing, which is on par with the best available methods. For comparison, we proposed a simple method using only the amino acid composition of proteins or peptides. This method has shown good results, at the level of the best methods. We have prepared a special server for predicting the ability of AMPs by amino acid composition: http://bioproteom.protres.ru/antimicrob/.

In the past years the interest in Solute Carrier Transporters (SLC) has increased due to their potential as drug targets. At the same time, macrocycles demonstrated promising activities as therapeutic agents. However, the overall macrocycle/SLC-transporter interaction landscape has not been fully revealed yet. In this study, we present a statistical analysis of macrocycles with measured activity against SLC-transporter. Using a data mining pipeline based on KNIME retrieved in total 825 bioactivity data points of macrocycles interacting with SLC-transporter. For further analysis of the SLC inhibitor profiles we developed an interactive KNIME workflow as well as an interactive map of the chemical space coverage utilizing parametric t-SNE models. The parametric t-SNE models provide a good discrimination ability among several corresponding SLC subfamilies' targets. The KNIME workflow, the dataset, and the visualization tool are freely available to the community.

Increasing antimicrobial resistance (AMR) represents a global healthcare threat. To decrease the spread of AMR and associated mortality, methods for rapid selection of optimal antibiotic treatment are urgently needed. Machine learning (ML) models based on genomic data to predict resistant phenotypes can serve as a fast screening tool prior to phenotypic testing. Nonetheless, many existing ML methods lack interpretability. Therefore, we present a methodology for visualization of sequence space and AMR prediction based on the non-linear dimensionality reduction method - generative topographic mapping (GTM). This approach, applied to AMR data of >5000 S. aureus isolates retrieved from the PATRIC database, yielded GTM models with reasonable accuracy for all drugs (balanced accuracy values ≥0.75). The Generative Topographic Maps (GTMs) represent data in the form of illustrative maps of the genomic space and allow for antibiotic-wise comparison of resistant phenotypes. The maps were also found to be useful for the analysis of genetic determinants responsible for drug resistance. Overall, the GTM-based methodology is a useful tool for both the illustrative exploration of the genomic sequence space and AMR prediction.