TTRMDB: A database for structural and functional analysis on the impact of SNPs over transthyretin (TTR) using bioinformatic tools

Hereditary Transthyretin-associated amyloidosis (ATTR) is an autosomal dominant protein-folding disorder with adult-onset caused by mutation of transthyretin (TTR). TTR is characterized by extracellular deposition of amyloid, leading to loss of autonomy and finally, death. More than 100 distinct mutations in TTR gene have been reported from variable age of onset, clinical expression and penetrance data. Besides, the cure for the disease remains still obscure. Further, the prioritizing of mutations concerning the characteristic features governing the stability and pathogenicity of TTR mutant proteins remains unanswered, to date and thus, a complex state of study for researchers. Herein, we provide a full report encompassing the effects of every reported mutant model of TTR protein about the stability, functionality and pathogenicity using various computational tools. In addition, the results obtained from our study were used to create TTRMDB (Transthyretin mutant database), which could be easy access to researchers at http://vit.ac.in/ttrmdb.     

ncRDeep: Non-coding RNA classification with convolutional neural network

A non-coding RNA (ncRNA) is a kind of RNA that is not converted into protein, however, it is involved in many biological processes, diseases, and cancers. Numerous ncRNAs have been identified and classified with high throughput sequencing technology. Hence, accurate ncRNAs class prediction is important and necessary for further study of their functions. Several computation techniques have been employed to predict the class of ncRNAs. Recent classification methods used the secondary structure as their primary input. However, the computational tools of RNA secondary structure are not accurate enough which affects the final performance of ncRNAs predictors. In this paper, we propose a simple yet efficient method, called ncRDeep, for ncRNAs prediction. It uses a simple convolutional neural network and RNA sequence information only. The ncRDeep was evaluated on benchmark datasets and the comparison results showed that the ncRDeep outperforms the state-of-the-art methods significantly. More specifically, the average accuracy was improved by 8.32%. Finally, we built a freely accessible web server for the developed tool ncRDeep at http://home.jbnu.ac.kr/NSCL/ncRDeep.htm     

Molecular docking,HOMO-LUMO and quantum chemical computation analysis of anti-glyoximehydrazone derivatives containing pyrazolone moiety and their transition metal complexes

In this study, in order to obtain biologically active compounds, a series of anti-glyoximehydrazone ligands bearing vic-dioxime, hydrazone, and pyrazole moieties and their (O•••H–O) bridged nickel(II), cobalt(II) and copper(II) metal complexes were prepared. Further, the molecular docking studies were carried out on those ligands and their nickel(II), cobalt(II) and copper(II) metal complexes to analyze the interaction with EGFR Kinase domain complexed with tak-285 (PDB ID: 3POZ) and human androgen receptor T877A mutant (PDB ID:2OZ7). In addition, the compounds were optimized by using B3LYP/6-311G+(d,p) level of Density Functional Theory (DFT) to evaluate the HOMO–LUMO contours and quantum chemical parameters. Also, bioactivity analysis were performed.Metal complexes had higher binding affinities against 3POZ and 2OZ7. The most promising compounds for 3POZ were nickel(II) and copper(II) metal complexes. However, for the 2OZ7 target receptor, cobalt(II) and copper(II) metal complexes were the possible hit compounds. Furthermore, cobalt(II) metal complex of ligand two was found to be the most reactive one among others. Moreover, it had the highest ω which is related to a potent higher electrophilic character. It was determined that all the compounds had moderate bioactivity.In conclusion, nickel(II), cobalt(II), and copper(II) complexes could be powerful hit compounds for anti-cancer drug discovery studies.     

Discovery of perturbation gene targets via free text metadata mining in Gene Expression Omnibus

There exists over 2.5 million publicly available gene expression samples across 101,000 data series in NCBI's Gene Expression Omnibus (GEO) database. Due to the lack of the use of standardised ontology terms in GEO's free text metadata to annotate the experimental type and sample type, this database remains difficult to harness computationally without significant manual intervention.In this work, we present an interactive R/Shiny tool called GEOracle that utilises text mining and machine learning techniques to automatically identify perturbation experiments, group treatment and control samples and perform differential expression. We present applications of GEOracle to discover conserved signalling pathway target genes and identify an organ specific gene regulatory network.GEOracle is effective in discovering perturbation gene targets in GEO by harnessing its free text metadata. Its effectiveness and applicability has been demonstrated by cross validation and two real-life case studies. It opens up new avenues to unlock the gene regulatory information embedded inside large biological databases such as GEO. GEOracle is available at https://github.com/VCCRI/GEOracle.     

FPDock: Protein–protein docking using flower pollination algorithm

Proteins play their vital role in biological systems through interaction and complex formation with other biological molecules. Indeed, abnormalities in the interaction patterns affect the proteins’ structure and have detrimental effects on living organisms. Research in structure prediction gains its gravity as the functions of proteins depend on their structures. Protein–protein docking is one of the computational methods devised to understand the interaction between proteins. Metaheuristic algorithms are promising to use owing to the hardness of the structure prediction problem. In this paper, a variant of the Flower Pollination Algorithm (FPA) is applied to get an accurate protein–protein complex structure. The algorithm begins execution from a randomly generated initial population, which gets flourished in different isolated islands, trying to find their local optimum. The abiotic and biotic pollination applied in different generations brings diversity and intensity to the solutions. Each round of pollination applies an energy-based scoring function whose value influences the choice to accept a new solution. Analysis of final predictions based on CAPRI quality criteria shows that the proposed method has a success rate of 58% in top10 ranks, which in comparison with other methods like SwarmDock, pyDock, ZDOCK is better. Source code of the work is available at: https://github.com/Sharon1989Sunny/_FPDock_.     

Efficient utilization on PSSM combining with recurrent neural network for membrane protein types prediction

Position-Specific Scoring Matrix (PSSM) is an excellent feature extraction method that was proposed early in protein classifying prediction, but within the restriction of feature shape in PSSM, researchers make a lot attempts to process it so that PSSM can be input to the traditional machine learning algorithms. These processes drop information provided by PSSM in a way thus the feature representation is limited. Moreover, the high-dimensional feature representation of PSSM makes it incompatible with other feature extraction methods. We use the PSSM as the input of Recurrent Neural Network without any post-processing, the amino acids in protein sequences are regarded as time step in RNN. This way takes full advantage of the information that PSSM provides. In this study, the PSSM is input to the model directly and the internal information of PSSM is fully utilized, we propose an end-to-end solution and achieve state-of-the-art performance. Ultimately, the exploration of how to combine PSSM with traditional feature extraction methods is carried out and achieve slightly improved performance. Our network architecture is implemented in Python and is available at https://github.com/YellowcardD/RNN-for-membrane-protein-types-prediction.     

RepEx: A web server to extract sequence repeats from protein and DNA sequences

Evolution builds up new genetic material from existing ones, not in random, but in highly ordered and eloquent patterns. Most of these sequence repeats are revelatory of valuable information contributing to areas of disease research and function of macromolecules, to name a few. In the age of next generation genome sequencing, rapid and efficient extraction of all unbiased sequence repeats from macromolecules is the need of the hour. In view of this reckoning, an online web-based computing server, RepEx, has been developed to extract and display all possible repeats for DNA and protein sequences. Apart from exact or identical repeats, the server has been designed adeptly to identify and extract degenerate, inverted, everted and mirror repeats from both DNA and protein sequences. The server has striking output displays, featuring interactive graphs and comprehensive output files. In addition, RepEx has been accoutered with an easy-to-use interface and search filters to facilitate a user-defined query or search and is freely available and accessible via the World Wide Web at http://bioserver2.physics.iisc.ac.in/RepEx/.     

A merged molecular docking,ADME-T and dynamics approaches towards the genus of Arisaema as herpes simplex virus type 1 and type 2 inhibitors

An attempt toward screening of phytoconstituents (Arisaema genus) against herpes viruses (HSV-1 and HSV-2) was carried out using in silico approaches. Human HSV-1 and HSV-2 are accountable for cold sores genital herpes, respectively. Two drug targets, namely thymidine kinase (TK; PDB: 2ki5) serine protease (PDB: 1at3) were selected for HSV-1 and HSV-2. Initially, molecular docking tool was employed to screened apex hits phytoconstituents against herpes infections. ADME-T studies of top ranked were also further highlighted to achieve their effectiveness. Following, molecular dynamics studies were also examined to further optimize the stability of ligands. Glide scores and binding interactions of phytoconstituents were compared with Acyclovir, the main drug used in treatment of HSV, the screened top hits exhibited more glide scores and better binding for both HSV-1 and HSV-2 receptors. Additionally, ADME-T showed an ideal range for top hits while molecular dynamics results also illustrated stability of models. Ultimately, the whole efforts reveal to top three most promising hits for HSV-1 (39, 21, 19) and HSV-2 (20, 51, 19) receptors which can be explored further in wet lab experiments as promising agents against HSV infections.     

Predicting potential miRNA-disease associations by combining gradient boosting decision tree with logistic regression

MicroRNAs (miRNAs) have been proved to play an indispensable role in many fundamental biological processes, and the dysregulation of miRNAs is closely correlated with human complex diseases. Many studies have focused on the prediction of potential miRNA-disease associations. Considering the insufficient number of known miRNA-disease associations and the poor performance of many existing prediction methods, a novel model combining gradient boosting decision tree with logistic regression (GBDT-LR) is proposed to prioritize miRNA candidates for diseases. To balance positive and negative samples, GBDT-LR firstly adopted k-means clustering to screen negative samples from unknown miRNA-disease associations. Then, the gradient boosting decision tree (GBDT) model, which has an intrinsic advantage in finding many distinguishing features and feature combinations is applied to extract features. Finally, the new features extracted by the GBDT model are input into a logistic regression (LR) model for predicting the final miRNA-disease association score. The experimental results show that the average AUC of GBDT-LR in 5-fold cross-validation (CV) can achieve 0.9274. Besides, in the case studies, 90 %, 94 % and 88 % of the top 50 miRNAs potentially associated with colon cancer, gastric cancer, and pancreatic cancer were confirmed by databases, respectively. Compared with the other three state-of-the-art methods, GBDT-LR can achieve the best prediction performance. The source code and dataset of GBDT-LR are freely available at https://github.com/Pualalala/GBDT-LR.     

Convolutional neural networks with image representation of amino acid sequences for protein function prediction

Proteins are one of the most important molecules that govern the cellular processes in most of the living organisms. Various functions of the proteins are of paramount importance to understand the basics of life. Several supervised learning approaches are applied in this field to predict the functionality of proteins. In this paper, we propose a convolutional neural network based approach ProtConv to predict the functionality of proteins by converting the amino-acid sequences to a two dimensional image. We have used a protein embedding technique using transfer learning to generate the feature vector. Feature vector is then converted into a square sized single channel image to be fed into a convolutional network. The neural network architecture used here is a combination of convolutional filters and average pooling layers followed by dense fully connected layers to predict a binary function. We have performed experiments on standard benchmark datasets taken from two very important protein function prediction task: proinflammatory cytokines and anticancer peptides. Our experiments show that the proposed method, ProtConv achieves state-of-the-art performances on both of the datasets. All necessary details about implementation with source code and datasets are made available at: https://github.com/swakkhar/ProtConv.     

Ligand based virtual screening using SVM on GPU

In silico methods play an essential role in modern drug discovery methods. Virtual screening, an in silico method, is used to filter out the chemical space on which actual wet lab experiments are need to be conducted. Ligand based virtual screening is a computational strategy using which one can build a model of the target protein based on the knowledge of the ligands that bind successfully to the target. This model is then used to predict if the new molecule is likely to bind to the target. Support vector machine, a supervised learning algorithm used for classification, can be utilized for virtual screening the ligand data. When used for virtual screening purpose, SVM could produce interesting results. But since we have a huge ligand data, the time taken for training the SVM model is quite high compared to other learning algorithms. By parallelizing these algorithms on multi-core processors, one can easily expedite these discoveries. In this paper, a GPU based ligand based virtual screening tool (GpuSVMScreen) which uses SVM have been proposed and bench-marked. This data parallel virtual screening tool provides high throughput by running in short time. The proposed GpuSVMScreen can successfully screen large number of molecules (billions) also. The source code of this tool is available at http://ccc.nitc.ac.in/project/GPUSVMSCREEN.     

predForm-Site: Formylation site prediction by incorporating multiple features and resolving data imbalance

Formylation is one of the newly discovered post-translational modifications in lysine residue which is responsible for different kinds of diseases. In this work, a novel predictor, named predForm-Site, has been developed to predict formylation sites with higher accuracy. We have integrated multiple sequence features for developing a more informative representation of formylation sites. Moreover, decision function of the underlying classifier have been optimized on skewed formylation dataset during prediction model training for prediction quality improvement. On the dataset used by LFPred and Formator predictor, predForm-Site achieved 99.5% sensitivity, 99.8% specificity and 99.8% overall accuracy with AUC of 0.999 in the jackknife test. In the independent test, it has also achieved more than 97% sensitivity and 99% specificity. Similarly, in benchmarking with recent method CKSAAP_FormSite, the proposed predictor significantly outperformed in all the measures, particularly sensitivity by around 20%, specificity by nearly 30% and overall accuracy by more than 22%. These experimental results show that the proposed predForm-Site can be used as a complementary tool for the fast exploration of formylation sites. For convenience of the scientific community, predForm-Site has been deployed as an online tool, accessible at http://103.99.176.239:8080/predForm-Site.     

Absorption and fluorescence spectra of open-chain tetrapyrrole pigments–bilirubins,biliverdins, phycobilins,and synthetic analogues

Open-chain tetrapyrroles are ubiquitous and abundant in living organisms (algae, animals, bacteria, and plants), including examples such as bilirubin, biliverdin, phycocyanobilin, phycoerythrobilin, and urobilin. The open-chain tetrapyrroles, collectively termed bilins, arise from biosynthesis or degradation of tetrapyrrole macrocycles. Bilins are now known to play a wide variety of biological roles encompassing light-harvesting (in phycobiliproteins), photomorphogenesis, signaling, and redox chemistry. The absorption spectra of bilins spans the ultraviolet (UV), visible, to near-infrared (NIR) regions depending on the degree of conjugation, thereby providing a wide range of colors from red/orange to blue/green. The fluorescence intensity of bilins is often quite low and hence fewer spectra are available, but can be increased substantially by structural rigidification, as evidenced by the wide use of biliproteins as fluorescent labels. The present article describes a database of absorption and fluorescence spectra of bilins from natural and synthetic origins for 220 compounds (270 absorption and 13 fluorescence spectral traces). Spectral traces of bilins published over the past ∼50 years have been digitized and assembled along with information concerning solvent, photochemical properties (molar absorption coefficient and fluorescence quantum yield), and literature references. The spectral traces (xy-coordinate data files) can be viewed, downloaded, and accessed at www.photochemcad.com. The accessibility of spectral traces in digital format should facilitate identification and quantitative calculations of interest in diverse scientific areas.     

Design,synthesis and characterization of a series of 6-substituted-4-hydroxy-1-(2-substitutedthiazol-4-yl)quinolin-2(1H)-one derivatives and evaluation of their in vitro anticancer and antibacterial activity

The current research work deals with the design, synthesis and characterization of a series of 6-substituted-4-hydroxy-1-(2-substitutedthiazol-4-yl)quinolin-2(1H)-one derivatives [III(a-d)(1–3)] and evaluation of their in-vitro anticancer activity against MDA-MB (Breast cancer) and A549 (Lung cancer) cell lines based upon MTT assay and in-vitro antibacterial by the measurement of zone of inhibition and determining the Minimum Inhibitory Concentration (MIC). All the synthesized compounds were characterized by UV, IR, ¹H NMR and ¹³C NMR spectral data.Molecular docking studies of the title compounds were carried out using Molegro Virtual Docker (MVD-2013, 6.0) software. The synthesized compounds exhibited well conserved hydrogen bond interactions with one or more amino acid residues in the active pocket of EGFRK tyrosine kinase domain (PDB ID: 1m17) for docking study on anticancer activity and S. aureus DNA Gyrase domain complexed with a ciprofloxacin inhibitor (PDB ID: 2XCT) for antibacterial docking study. All synthesized derivatives were potent against A549 (Lung cancer) cell line as compared to MDA-MB (Breast cancer) cell line. Compound 2-(4-(4-hydroxy-6-methyl-2-oxoquinolin-1(2H)-yl)thiazol-2-yl)hydrazin-1-ium iodide (IIId-2) was found to be the most cytotoxic as compared to the other synthesized derivatives, with IC₅₀ values of 346.12 μg/mL against A549 (Lung cancer) cell line, however all synthesized derivatives were found to be a poor antibacterial agent when compared with standard ciprofloxacin.Thus, the synthesized derivatives possessed a potential to bind with some of the residues of the active site and can be further developed into potential pharmacological agents.     

Cnngeno: A high-precision deep learning based strategy for the calling of structural variation genotype

Genotype plays a significant role in determining characteristics in an organism and genotype calling has been greatly accelerated by sequencing technologies. Furthermore, most parametric statistical models are unable to effectively call genotype, which is influenced by the size of structural variations and the coverage fluctuations of sequencing data. In this study, we propose a new method for calling deletions’ genotypes from the next-generation data, called Cnngeno. Cnngeno can convert sequencing data into images and classifies the genotypes from these images using the convolutional neural network(CNN). Moreover, Cnngeno adopted the convolutional bootstrapping strategy to improve the anti-noisy label’s ability. The results show that Cnngeno performs better in terms of precision for calling genotype when compared with other existing methods. The Cnngeno is an open-source method, available at https://github.com/BRF123/Cnngeno.     

FWAVina: A novel optimization algorithm for protein-ligand docking based on the fireworks algorithm

Protein-ligand docking is an essential process that has accelerated drug discovery. How to accurately and effectively optimize the predominant position and orientation of ligands in the binding pocket of a target protein is a major challenge. This paper proposed a novel ligand binding pose search method called FWAVina based on the fireworks algorithm, which combined the fireworks algorithm with the efficient Broyden-Fletcher-Goldfarb-Shannon local search method adopted in AutoDock Vina to address the pose search problem in docking. The FWA was used as a global optimizer to rapidly search promising poses, and the Broyden-Fletcher-Goldfarb-Shannon method was incorporated into FWAVina to perform an exact local search. FWAVina was developed and tested on the PDBbind and DUD-E datasets. The docking performance of FWAVina was compared with the original Vina program. The results showed that FWAVina achieves a remarkable execution time reduction of more than 50 % than Vina without compromising the prediction accuracies in the docking and virtual screening experiments. In addition, the increase in the number of ligand rotatable bonds has almost no effect on the efficiency of FWAVina. The higher accuracy, faster convergence and improved stability make the FWAVina method a better choice of docking tool for computer-aided drug design. The source code is available at https://github.com/eddyblue/FWAVina/.