Application of network link prediction in drug discovery

BackgroundTechnological and research advances have produced large volumes of biomedical data. When represented as a network (graph), these data become useful for modeling entities and interactions in biological and similar complex systems. In the field of network biology and network medicine, there is a particular interest in predicting results from drug–drug, drug–disease, and protein–protein interactions to advance the speed of drug discovery. Existing data and modern computational methods allow to identify potentially beneficial and harmful interactions, and therefore, narrow drug trials ahead of actual clinical trials. Such automated data-driven investigation relies on machine learning techniques. However, traditional machine learning approaches require extensive preprocessing of the data that makes them impractical for large datasets. This study presents wide range of machine learning methods for predicting outcomes from biomedical interactions and evaluates the performance of the traditional methods with more recent network-based approaches.ResultsWe applied a wide range of 32 different network-based machine learning models to five commonly available biomedical datasets, and evaluated their performance based on three important evaluations metrics namely AUROC, AUPR, and F1-score. We achieved this by converting link prediction problem as binary classification problem. In order to achieve this we have considered the existing links as positive example and randomly sampled negative examples from non-existant set. After experimental evaluation we found that Prone, ACT an

Glycation of H1 Histone by 3-Deoxyglucosone: Effects on Protein Structure and Generation of Different Advanced Glycation End Products

<div><p>Advanced glycation end products (AGEs) culminate from the non-enzymatic reaction between a free carbonyl group of a reducing sugar and free amino group of proteins. 3-deoxyglucosone (3-DG) is one of the dicarbonyl species that rapidly forms several protein-AGE complexes that are believed to be involved in the pathogenesis of several diseases, particularly diabetic complications. In this study, the generation of AGEs (N^ε-carboxymethyl lysine and pentosidine) by 3-DG in H1 histone protein was characterized by evaluating extent of side chain modification (lysine and arginine) and formation of Amadori products as well as carbonyl contents using several physicochemical techniques. Results strongly suggested that 3-DG is a potent glycating agent that forms various intermediates and AGEs during glycation reactions and affects the secondary structure of the H1 protein. Structural changes and AGE formation may influence the function of H1 histone and compromise chromatin structures in cases of secondary diabetic complications.</p></div

3-Deoxyglucosone: a potential glycating agent accountable for structural alteration in H3 histone protein through generation of different AGEs.

Advanced glycation end-products (AGEs) are heterogeneous group of compounds, known to be implicated in diabetic complications. One of the consequences of the Maillard reaction is attributed to the production of reactive intermediate products such as α-oxoaldehydes. 3-deoxyglucosone (3-DG), an α-oxoaldehyde has been found to be involved in accelerating vascular damage during diabetes. In the present study, calf thymus histone H3 was treated with 3-deoxyglucosone to investigate the generation of AGEs (Nε-carboxymethyllysine, pentosidine), by examining the degree of side chain modifications and formation of different intermediates and employing various physicochemical techniques. The results clearly indicate the formation of AGEs and structural changes upon glycation of H3 by 3-deoxyglucosone, which may hamper the normal functioning of H3 histone, that may compromise the veracity of chromatin structures and function in secondary complications of diabetes

Far-UV CD spectra of native (—) and 3-DG-glycated H1 histone (- - -).

<p>The spectra were recorded between 200 and 250 nm. The protein concentration was 0.5 mg/ml and the path-length was 1.0 cm.</p

Temperature-induced denaturation spectral profiles demonstrating alteration in ellipticity at 208 nm of native (—) and 3-DG-glycated H1 histone (-—-).

<p>Temperature-induced denaturation spectral profiles demonstrating alteration in ellipticity at 208 nm of native (—) and 3-DG-glycated H1 histone (-—-).</p

UV-Vis spectral profiles of native (—) and 3-DG- glycated H1 histone (- - - -).

<p>UV-Vis spectral profiles of native (—) and 3-DG- glycated H1 histone (- - - -).</p

HPLC study of native and 3-DG-glycated H1 histone protein.

<p>(A) Chromatograms for native H1, (B and C) standard CML and pentosidine, and (D) glycated H1 protein.</p

Formation of various intermediates and AGEs.

<p>Formation of various intermediates and AGEs.</p

UV-Vis spectral analysis of native (---) and 3-DG-glycated (- - - -) H3 histone.

<p>UV-Vis spectral analysis of native (---) and 3-DG-glycated (- - - -) H3 histone.</p

CD spectral, thermal denaturation and FTIR profile of native (---) and 3-DG-glycated (- - - -) H3 histone; (A) Far-UV CD profiles, (B) thermal denaturation showing changes in ellipticity at 222 nm, and (C) FTIR profiles of Amide I and Amide II bands corresponding to native H3 histones and 3-DG-glycated H3 histone.

<p>CD spectral, thermal denaturation and FTIR profile of native (---) and 3-DG-glycated (- - - -) H3 histone; (A) Far-UV CD profiles, (B) thermal denaturation showing changes in ellipticity at 222 nm, and (C) FTIR profiles of Amide I and Amide II bands corresponding to native H3 histones and 3-DG-glycated H3 histone.</p