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•Isolated ceramides (1) from Cissus incisa leaves are new within genus.•Ceramides (1) were more active against carbapenems-resistant Acinetobacter baumannii.•Molecular docking showed ...that ceramides (1) target on Gram-negative cell membrane.•Biophysical assay shown that (1) disturb membrane permeability without lithic action.•The set of obtained results allows to state a preliminary mechanism of action.
The developing of antibacterial resistance is becoming in crisis. In this sense, natural products play a fundamental role in the discovery of antibacterial agents with diverse mechanisms of action. Phytochemical investigation of Cissus incisa leaves led to isolation and characterization of the ceramides mixture (1): (8E)-2-(tritriacont-9-enoyl amino)-1,3,4-octadecanetriol-8-ene (1-I); (8E)-2-(2',3'-dihydroxyoctacosanoyl amino)-1,3,4-octadecanetriol-8-ene (1-II); (8E)-2-(2'-hydroxyheptacosanoyl amino)-1,3,4-octadecanetriol-8-ene (1-III); and (8E)-2-(-2'-hydroxynonacosanoyl amino)-1,3,4-octadecanetriol-8-ene (1-IV). Until now, this is the first report of the ceramides (1-I), (1-II), and (1-IV). The structures were elucidated using NMR and mass spectrometry analyses. Antibacterial activity of ceramides (1) and acetylated derivates (2) was evaluated against nine multidrug-resistant bacteria by Microdilution method. (1) showed the best results against Gram-negatives, mainly against carbapenems-resistant Acinetobacter baumannii with MIC = 50 μg/mL. Structure-activity analysis and molecular docking revealed interactions between plant ceramides with membrane proteins, and enzymes associated with biological membranes of Gram-negative bacteria, through hydrogen bonding of functional groups. Vesicular contents release assay showed the capacity of (1) to disturb membrane permeability detected by an increase of fluorescence probe over time. The membrane disruption is not caused for ceramides lytic action on cell membranes, according in vitro hemolyticactivity results. Combining SAR analysis, bioinformatics and biophysical techniques, and also experimental tests, it was possible to explain the antibacterial action of these natural ceramides.
•CoEnBPs play a vital role in fatty acid biosynthesis, gene regulation, and lipid synthesis, etc.•In silico screening of a new peptide with coenzyme binding activity might be an efficient process.•A ...dataset of 42 SGTI features for 2,897 proteins (456 CoEnBPs) was used as inputs to construct classification models.•Best model obtained with 3 SGTI features in RF model with 0.971 (AUROC), 91.7% (TP rate), and 7.6% (FP rate).•ML models for predicting new CoEnBPs could be useful for future drug development or enzyme catalysis metabolism research.
The coenzyme-binding proteins play a vital role in the cellular metabolism processes, such as fatty acid biosynthesis, enzyme and gene regulation, lipid synthesis, particular vesicular traffic, and β-oxidation donation of acyl-CoA esters. Based on the theory of Star Graph Topological Indices (SGTIs) of protein primary sequences, we proposed a method to develop a first classification model for predicting protein with coenzyme-binding properties. To simulate the properties of coenzyme-binding proteins, we created a dataset containing 2897 proteins, among 456 proteins functioned as coenzyme-binding activity. The SGTIs of peptide sequence were calculated with Sequence to Star Network (S2SNet) application. We used the SGTIs as inputs to several classification techniques with a machine learning software - Weka. A Random Forest classifier based on 3 features of the embedded and non-embedded graphs was identified as the best predictive model for coenzyme-binding proteins. This model developed was with the true positive (TP) rate of 91.7%, false positive (FP) rate of 7.6%, and Area Under the Receiver Operating Characteristic Curve (AUROC) of 0.971. The prediction of new coenzyme-binding activity proteins using this model could be useful for further drug development or enzyme metabolism researches.
Sarcomas are a group of malignant neoplasms of connective tissue with a different etiology than carcinomas. The efforts to discover new drugs with antisarcoma activity have generated large datasets ...of multiple preclinical assays with different experimental conditions. For instance, the ChEMBL database contains outcomes of 37,919 different antisarcoma assays with 34,955 different chemical compounds. Furthermore, the experimental conditions reported in this dataset include 157 types of biological activity parameters, 36 drug targets, 43 cell lines, and 17 assay organisms. Considering this information, we propose combining perturbation theory (PT) principles with machine learning (ML) to develop a PTML model to predict antisarcoma compounds. PTML models use one function of reference that measures the probability of a drug being active under certain conditions (protein, cell line, organism, etc.). In this paper, we used a linear discriminant analysis and neural network to train and compare PT and non-PT models. All the explored models have an accuracy of 89.19–95.25% for training and 89.22–95.46% in validation sets. PTML-based strategies have similar accuracy but generate simplest models. Therefore, they may become a versatile tool for predicting antisarcoma compounds.
The electrokinetic properties of the rumen microbiota are involved in cell surface adhesion and microbial metabolism. An
study was carried out in batch culture to determine the effects of three ...levels of special surface area (SSA) of biomaterials and four levels of surface tension (ST) of culture medium on electrokinetic properties (Zeta potential, ξ; electrokinetic mobility, μ
), fermentation parameters (volatile fatty acids, VFAs), and ST over fermentation processes (ST-a, γ). The obtained results were combined with previously published data (digestibility, D; pH; concentration of ammonia nitrogen, c(NH
-N)) to establish a predictive artificial neural network (ANN) model. Concepts of dual-time series analysis, perturbation theory (PT), and Box-Jenkins Operators were applied for the first time to develop an ANN model to predict the variations of the electrokinetic properties of microbiota. The best dual-time series Radial Basis Functions (RBR) model for ξ of rumen microbiota predicted ξ for >30,000 cases with a correlation coefficient >0.8. This model provided insight into the correlations between electrokinetic property (zeta potential) of rumen microbiota and the perturbations of physical factors (specific surface area and surface tension) of media, digestibility of substrate, and their metabolites (NH
-N, VFAs) in relation to environmental factors.
Graph and Complex Network theory is expanding its application to different levels of matter organization such as molecular, biological, technological, and social networks. A network is a set of ...items, usually called nodes, with connections between them, which are called links or edges. There are many different experimental and/or theoretical methods to assign node–node links depending on the type of network we want to construct. Unfortunately, the use of a method for experimental reevaluation of the entire network is very expensive in terms of time and resources; thus the development of cheaper theoretical methods is of major importance. In addition, different methods to link nodes in the same type of network are not totally accurate in such a way that they do not always coincide. In this sense, the development of computational methods useful to evaluate connectivity quality in complex networks (a posteriori of network assemble) is a goal of major interest. In this work, we report for the first time a new method to calculate numerical quality scores S(Lij) for network links Lij (connectivity) based on the Markov–Shannon Entropy indices of order k-th (θk) for network nodes. The algorithm may be summarized as follows: (i) first, the θk(j) values are calculated for all j-th nodes in a complex network already constructed; (ii) A Linear Discriminant Analysis (LDA) is used to seek a linear equation that discriminates connected or linked (Lij=1) pairs of nodes experimentally confirmed from non-linked ones (Lij=0); (iii) the new model is validated with external series of pairs of nodes; (iv) the equation obtained is used to re-evaluate the connectivity quality of the network, connecting/disconnecting nodes based on the quality scores calculated with the new connectivity function. This method was used to study different types of large networks. The linear models obtained produced the following results in terms of overall accuracy for network reconstruction: Metabolic networks (72.3%), Parasite–Host networks (93.3%), CoCoMac brain cortex co-activation network (89.6%), NW Spain fasciolosis spreading network (97.2%), Spanish financial law network (89.9%) and World trade network for Intelligent & Active Food Packaging (92.8%). In order to seek these models, we studied an average of 55,388 pairs of nodes in each model and a total of 332,326 pairs of nodes in all models. Finally, this method was used to solve a more complicated problem. A model was developed to score the connectivity quality in the Drug–Target network of US FDA approved drugs. In this last model the θk values were calculated for three types of molecular networks representing different levels of organization: drug molecular graphs (atom–atom bonds), protein residue networks (amino acid interactions), and drug–target network (compound–protein binding). The overall accuracy of this model was 76.3%. This work opens a new door to the computational reevaluation of network connectivity quality (collation) for complex systems in molecular, biomedical, technological, and legal–social sciences as well as in world trade and industry.
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► Markov–Shannon Entropy method to re-evaluate links in networks. ► Accuracy of 93.3% for Host–Parasite relations and 97.2 for Parasite spreading. ► Accuracy of 99.2 for metabolic pathways and 89.6 for brain network. ► Re-evaluation of Spanish Financial Law system network with an accuracy of 89.91. ► Models with an accuracy of 92.8 for Food Packaging and 76.3 for Drug–Target network.
Evolutionary computation and QSAR research Aguiar-Pulido, Vanessa; Gestal, Marcos; Cruz-Monteagudo, Maykel ...
Current computer-aided drug design,
06/2013, Letnik:
9, Številka:
2
Journal Article
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The successful high throughput screening of molecule libraries for a specific biological property is one of the main improvements in drug discovery. The virtual molecular filtering and screening ...relies greatly on quantitative structure-activity relationship (QSAR) analysis, a mathematical model that correlates the activity of a molecule with molecular descriptors. QSAR models have the potential to reduce the costly failure of drug candidates in advanced (clinical) stages by filtering combinatorial libraries, eliminating candidates with a predicted toxic effect and poor pharmacokinetic profiles, and reducing the number of experiments. To obtain a predictive and reliable QSAR model, scientists use methods from various fields such as molecular modeling, pattern recognition, machine learning or artificial intelligence. QSAR modeling relies on three main steps: molecular structure codification into molecular descriptors, selection of relevant variables in the context of the analyzed activity, and search of the optimal mathematical model that correlates the molecular descriptors with a specific activity. Since a variety of techniques from statistics and artificial intelligence can aid variable selection and model building steps, this review focuses on the evolutionary computation methods supporting these tasks. Thus, this review explains the basic of the genetic algorithms and genetic programming as evolutionary computation approaches, the selection methods for high-dimensional data in QSAR, the methods to build QSAR models, the current evolutionary feature selection methods and applications in QSAR and the future trend on the joint or multi-task feature selection methods.
Brain Connectome Networks (BCNs) are defined by brain cortex regions (nodes) interacting with others by electrophysiological co-activation (edges). The experimental prediction of new interactions in ...BCNs represents a difficult task due to the large number of edges and the complex connectivity patterns. Fortunately, we can use another special type of networks to achieve this goal—Artificial Neural Networks (ANNs). Thus, ANNs could use node descriptors such as Shannon Entropies (Sh) to predict node connectivity for large datasets including complex systems such as BCN. However, the training of a high number of ANNs for BCNs is a time-consuming task. In this work, we propose the use of a method to automatically determine which ANN topology is more efficient for the BCN prediction. Since a network (ANN) is used to predict the connectivity in another network (BCN), this method was entitled Net-Net AutoML. The algorithm uses Sh descriptors for pairs of nodes in BCNs and for ANN predictors of BCNs. Therefore, it is able to predict the efficiency of new ANN topologies to predict BCNs. The current study used a set of 500,470 examples from 10 different ANNs to predict node connectivity in BCNs and 20 features. After testing five Machine Learning classifiers, the best classification model to predict the ability of an ANN to evaluate node interactions in BCNs was provided by Random Forest (mean test AUROC of 0.9991 ± 0.0001, 10-fold cross-validation). Net-Net AutoML algorithms based on entropy descriptors may become a useful tool in the design of automatic expert systems to select ANN topologies for complex biological systems. The scripts and dataset for this project are available in an open GitHub repository.
Many drugs with very different affinity to a large number of receptors are described. Thus, in this work, we selected drug−target pairs (DTPs/nDTPs) of drugs with high affinity/nonaffinity for ...different targets. Quantitative structure−activity relationship (QSAR) models become a very useful tool in this context because they substantially reduce time and resource-consuming experiments. Unfortunately, most QSAR models predict activity against only one protein target and/or they have not been implemented on a public Web server yet, freely available online to the scientific community. To solve this problem, we developed a multitarget QSAR (mt-QSAR) classifier combining the MARCH-INSIDE software for the calculation of the structural parameters of drug and target with the linear discriminant analysis (LDA) method in order to seek the best model. The accuracy of the best LDA model was 94.4% (3,859/4,086 cases) for training and 94.9% (1,909/2,012 cases) for the external validation series. In addition, we implemented the model into the Web portal Bio-AIMS as an online server entitled MARCH-INSIDE Nested Drug-Bank Exploration & Screening Tool (MIND-BEST), located at http://miaja.tic.udc.es/Bio-AIMS/MIND-BEST.php. This online tool is based on PHP/HTML/Python and MARCH-INSIDE routines. Finally, we illustrated two practical uses of this server with two different experiments. In experiment 1, we report for the first time a MIND-BEST prediction, synthesis, characterization, and MAO-A and MAO-B pharmacological assay of eight rasagiline derivatives, promising for anti-Parkinson drug design. In experiment 2, we report sampling, parasite culture, sample preparation, 2-DE, MALDI-TOF and -TOF/TOF MS, MASCOT search, 3D structure modeling with LOMETS, and MIND-BEST prediction for different peptides as new protein of the found in the proteome of the bird parasite Trichomonas gallinae, which is promising for antiparasite drug targets discovery.
The cell death (CD) is a dynamic biological function involved in physiological and pathological processes. Due to the complexity of CD, there is a demand for fast theoretical methods that can help to ...find new CD molecular targets. The current work presents the first classification model to predict CD-related proteins based on Markov Mean Properties. These protein descriptors have been calculated with the MInD-Prot tool using the topological information of the amino acid contact networks of the 2423 protein chains, five atom physicochemical properties and the protein 3D regions. The Machine Learning algorithms from Weka were used to find the best classification model for CD-related protein chains using all 20 attributes. The most accurate algorithm to solve this problem was K*. After several feature subset methods, the best model found is based on only 11 variables and is characterized by the Area Under the Receiver Operating Characteristic Curve (AUROC) of 0.992 and the true positive rate (TP Rate) of 88.2% (validation set). 7409 protein chains labeled with “unknown function” in the PDB Databank were analyzed with the best model in order to predict the CD-related biological activity. Thus, several proteins have been predicted to have CD-related function in Homo sapiens: 3DRX–involved in virus-host interaction biological process, protein homooligomerization; 4DWF–involved in cell differentiation, chromatin modification, DNA damage response, protein stabilization; 1IUR–involved in ATP binding, chaperone binding; 1J7D–involved in DNA double-strand break processing, histone ubiquitination, nucleotide-binding oligomerization; 1UTU–linked with DNA repair, regulation of transcription; 3EEC–participating to the cellular membrane organization, egress of virus within host cell, class mediator resulting in cell cycle arrest, negative regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle and apoptotic process. Other proteins from bacteria predicted as CD-related are 2G3V - a CAG pathogenicity island protein 13 from Helicobacter pylori, 4G5A - a hypothetical protein in Bacteroides thetaiotaomicron, 1YLK–involved in the nitrogen metabolism of Mycobacterium tuberculosis, and 1XSV - with possible DNA/RNA binding domains. The results demonstrated the possibility to predict CD-related proteins using molecular information encoded into the protein 3D structure. Thus, the current work demonstrated the possibility to predict new molecular targets involved in cell-death processes.
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•We present the first QSAR classification model to predict cell death-related proteins.•We used Markov mean properties calculated with the MInD-Prot software.•We propose a model based on K* algorithm and 11 variables.•The classifier is characterized by the AUROC of 0.992 and TP Rate of 88.2%.•We screen 7409 “unknown function” protein chains for cell death biological activity.
There is pressing urgency to identify therapeutic targets and drugs that allow treating COVID-19 patients effectively.
We performed
analyses of immune system protein interactome network, single-cell ...RNA sequencing of human tissues, and artificial neural networks to reveal potential therapeutic targets for drug repurposing against COVID-19.
We screened 1,584 high-confidence immune system proteins in ACE2 and TMPRSS2 co-expressing cells, finding 25 potential therapeutic targets significantly overexpressed in nasal goblet secretory cells, lung type II pneumocytes, and ileal absorptive enterocytes of patients with several immunopathologies. Then, we performed fully connected deep neural networks to find the best multitask classification model to predict the activity of 10,672 drugs, obtaining several approved drugs, compounds under investigation, and experimental compounds with the highest area under the receiver operating characteristics.
After being effectively analyzed in clinical trials, these drugs can be considered for treatment of severe COVID-19 patients. Scripts can be downloaded at https://github.com/muntisa/immuno-drug-repurposing-COVID-19.
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