Artificial intelligence in the life sciences最新文献

The lack of bioinformatics tools to quickly assess protein conformational and topological features motivated to create an integrative and user-friendly R package. Moreover, the Fiscore package implements a pipeline for Gaussian mixture modelling making such machine learning methods readily accessible to non-experts. This is especially important since probabilistic machine learning techniques can help with a better interpretation of complex biological phenomena when it is necessary to elucidate various structural features that might play a role in protein function. Thus, Fiscore builds on the mathematical formulation of protein physicochemical properties that can aid in drug discovery, target evaluation, or relational database building. In addition, the package provides interactive environments to explore various features of interest. Finally, one of the goals of this package was to engage structural bioinformaticians and develop more robust and free R tools that could help researchers not necessarily specialising in this field. Package Fiscore (v.0.1.3) is distributed free of charge via CRAN and Github.

Deep learning is very promising in solving problems in omics research, such as genomics, epigenomics, proteomics, and metabolics. The design of neural network architecture is very important in modeling omics data against different scientific problems. Residual fully-connected neural network (RFCN) was proposed to provide better neural network architectures for modeling omics data. The next challenge for omics research is how to integrate information from different omics data using deep learning, so that information from different molecular system levels could be combined to predict the target. In this paper, we present a novel multi-omics integration approach named AutoOmics that could efficiently integrate information from different omics data and achieve better accuracy than previous approaches. We evaluated our method on four different tasks: drug repositioning, target gene prediction, breast cancer subtyping and cancer type prediction, and all the four tasks achieved state of art performances.

Bile salt export pump (BSEP) is a transporter that moves bile salts from hepatocytes into bile canaliculi. BSEP inhibition can result in the toxic accumulation of bile salts in the liver, which has been identified as a risk factor of drug-induced liver injury (DILI). Since DILI is a frequent cause of drug withdrawals from the market or failings in drug development, in vitro BSEP activity is measured with the [³H]taurocholate uptake assay and a half-maximal inhibitory concentration (IC₅₀) higher than 30 µM is advised. Herein, a machine learning classification model was developed to accurately detect BSEP inhibitors and help in the prioritization of in vitro testing. Regression models for the numerical prediction of IC₅₀ values were also generated. Classification and regression models for BSEP inhibition have been evaluated on realistic settings, which is critical prior to ML-based decision making in drug discovery programs. This work illustrates how predictive safety can help in early toxicity risk assessment and compound prioritization by leveraging Novartis historical experimental data.

Compounds interfering with high-throughput screening (HTS) assay technologies (also known as “badly behaving compounds”, “bad actors”, “nuisance compounds” or “PAINS”) pose a major challenge to early-stage drug discovery. Many of these problematic compounds are “frequent hitters”, and we have recently published a set of machine learning models (“Hit Dexter 2.0”) for flagging such compounds.

Here we present a new generation of machine learning models which are derived from a large, manually curated and annotated data set. For the first time, these models cover, in addition to target-based assays, also cell-based assays. Our experiments show that cell-based assays behave indeed differently from target-based assays, with respect to hit rates and frequent hitters, and that dedicated models are required to produce meaningful predictions. In addition to these extensions and refinements, we explored a variety of additional setups for modeling, including the combination of four machine learning classifiers (i.e. k-nearest neighbors (KNN), extra trees, random forest and multilayer perceptron) with four sets of descriptors (Morgan2 fingerprints, Morgan3 fingerprints, MACCS keys and 2D physicochemical property descriptors).

Testing on holdout data as well as data sets of “dark chemical matter” (i.e. compounds that have been extensively tested in biological assays but have never shown activity) and known bad actors show that the multilayer perceptron classifiers in combination with Morgan2 fingerprints outperform other setups in most cases. The best multilayer perceptron classifiers obtained Matthews correlation coefficients of up to 0.648 on holdout data. These models are available via a free web service.

The search for novel therapeutic compounds remains an overwhelming task owing to the time-consuming and expensive nature of the drug development process and low success rates. Traditional methodologies that rely on the one drug-one target paradigm have proven insufficient for the treatment of multifactorial diseases, leading to a shift to multitarget approaches. In this emerging paradigm, molecules with off-target and promiscuous interactions may result in preferred therapies. In this study, we developed a general pipeline combining machine learning algorithms and a deep generator network to train a dual inhibitor classifier capable of identifying putative pharmacophoric traits. As a case study, we focused on dual inhibitors targeting DNA methyltransferase 1 (DNMT) and histone deacetylase 2 (HDAC2), two enzymes that play a central role in epigenetic regulation. We used this approach to identify dual inhibitors from a novel large natural product database in the public domain. We used docking and atomistic simulations as complementary approaches to establish the ligand-interaction profiles between the best hits and DNMT1/HDAC2. By using the combined ligand- and structure-based approaches, we discovered two promising novel scaffolds that can be used to simultaneously target both DNMT1 and HDAC2. We conclude that the flexibility and adaptability of the proposed pipeline has predictive capabilities of similar or derivative methods and is readily applicable to the discovery of small molecules targeting many other therapeutically relevant proteins.

Eye irritation and corrosion are fundamental considerations in developing chemicals to be used in or near the eye, from cleaning products to ophthalmic solutions. Unfortunately, animal testing is currently the standard method to identify compounds that cause eye irritation or corrosion. Yet, there is growing pressure on the part of regulatory agencies both in the USA and abroad to develop New Approach Methodologies (NAMs) that help reduce the need for animal testing and address unmet need to modernize safety evaluation of chemical hazards. In furthering the development and applications of computational NAMs in chemical safety assessment, in this study we have collected the largest expertly curated dataset of compounds tested for eye irritation and corrosion, and employed this data to build and validate binary and multi-classification Quantitative Structure-Activity Relationships (QSAR) models that can reliably assess eye irritation/corrosion potential of novel untested compounds. QSAR models were generated with Random Forest (RF) and Multi-Descriptor Read Across (MuDRA) machine learning (ML) methods, and validated using a 5-fold external cross-validation protocol. These models demonstrated high balanced accuracy (CCR of 0.68–0.88), sensitivity (SE of 0.61–0.84), positive predictive value (PPV of 0.65–0.90), specificity (SP of 0.56–0.91), and negative predictive value (NPV of 0.68–0.85). Overall, MuDRA models outperformed RF models and were applied to predict compounds’ irritation/corrosion potential from the Inactive Ingredient Database, which contains components present in FDA-approved drug products, and from the Cosmetic Ingredient Database, the European Commission source of information on cosmetic substances. All models built and validated in this study are publicly available at the STopTox web portal (https://stoptox.mml.unc.edu/). These models can be employed as reliable tools for identifying potential eye irritant/corrosive compounds.

Active learning has been widely used in drug discovery and design in recent years. In this viewpoint, we will briefly summarize applications of AL for drug discovery and propose two potential limitations of research in this field.

Food is considered as a basic need of human being which can be satisfied through farming. Agriculture not only fulfills humans’ basic needs, but also considered as source of employment worldwide. Agriculture is considered as a backbone of economy and source of employment in the developing countries like India. Agriculture contributes 15.4% in the GDP of India. Agriculture activities are broadly categorized into three major areas: pre-harvesting, harvesting and post harvesting. Advancement in area of machine learning has helped improving gains in agriculture. Machine learning is the current technology which is benefiting farmers to minimize the losses in the farming by providing rich recommendations and insights about the crops. This paper presents an extensive survey of latest machine learning application in agriculture to alleviate the problems in the three areas of pre-harvesting, harvesting and post-harvesting. Application of machine learning in agriculture allows more efficient and precise farming with less human manpower with high quality production.