DDI-CPI, a server that predicts drug–drug interactions through implementing the chemical–protein interactome

Drug–drug interactions (DDIs) may cause serious side-effects that draw great attention from both academia and industry. Since some DDIs are mediated by unexpected drug–human protein interactions, it is reasonable to analyze the chemical–protein interactome (CPI) profiles of the drugs to predict their DDIs. Here we introduce the DDI-CPI server, which can make real-time DDI predictions based only on molecular structure. When the user submits a molecule, the server will dock user's molecule across 611 human proteins, generating a CPI profile that can be used as a feature vector for the pre-constructed prediction model. It can suggest potential DDIs between the user's molecule and our library of 2515 drug molecules. In cross-validation and independent validation, the server achieved an AUC greater than 0.85. Additionally, by investigating the CPI profiles of predicted DDI, users can explore the PK/PD proteins that might be involved in a particular DDI. A 3D visualization of the drug-protein interaction will be provided as well. The DDI-CPI is freely accessible at http://cpi.bio-x.cn/ddi/

Identification of neprilysin as a potential target of arteannuin using computational drug repositioning

The discovery of arteannuin (qinghaosu) in the 20th Century was a major advance for medicine. Besides functioning as a malaria therapy, arteannuin is a pharmacological agent in a range of other diseases, but its mechanism of action remains obscure. In this study, the reverse docking server PharmMapper was used to identify potential targets of arteannuin. The results were checked using the chemical-protein interactome servers DRAR-CPI and DDI-CPI, and verified by AutoDock Vina. The results showed that neprilysin (also known as CD10), a common acute lymphoblastic leukaemia antigen, was the top disease-related target of arteannuin. The chemical-protein interactome and docking results agreed with those of PharmMapper, further implicating neprilysin as a potential target. Although experimental verification is required, this study provides guidance for future pharmacological investigations into novel clinical applications for arteannuin

Predicting drug–drug interactions through drug structural similarities and interaction networks incorporating pharmacokinetics and pharmacodynamics knowledge

Additional file 1. Table S1. Average structural similarity scores for the DDI/non–DDI pairs in the network of each De. Table S2-1. Top 10 predicted drugs with DDIs for warfarin. Table S2-2. Top 10 predicted drugs with DDIs for simvastatin. Table S3. Four-fold cross-validation test results. Text S1. Drugs that show DDI (DrugBank ID). Figure S1. Illustration of construction of training and test set for 4-fold cross validation. Figure S2. ROC curves using the models with score set 1 in a 4-fold validation

Applications of Data Mining in Healthcare

Indiana University-Purdue University Indianapolis (IUPUI)With increases in the quantity and quality of healthcare related data, data mining tools have the potential to improve people’s standard of living through personalized and predictive medicine. In this thesis we improve the state-of-the-art in data mining for several problems in the healthcare domain. In problems such as drug-drug interaction prediction and Alzheimer’s Disease (AD) biomarkers discovery and prioritization, current methods either require tedious feature engineering or have unsatisfactory performance. New effective computational tools are needed that can tackle these complex problems. In this dissertation, we develop new algorithms for two healthcare problems: high-order drug-drug interaction prediction and amyloid imaging biomarker prioritization in Alzheimer’s Disease. Drug-drug interactions (DDIs) and their associated adverse drug reactions (ADRs) represent a significant detriment to the public h ealth. Existing research on DDIs primarily focuses on pairwise DDI detection and prediction. Effective computational methods for high-order DDI prediction are desired. In this dissertation, I present a deep learning based model D 3 I for cardinality-invariant and order-invariant high-order DDI pre- diction. The proposed models achieve 0.740 F1 value and 0.847 AUC value on high-order DDI prediction, and outperform classical methods on order-2 DDI prediction. These results demonstrate the strong potential of D 3 I and deep learning based models in tackling the prediction problems of high-order DDIs and their induced ADRs. The second problem I consider in this thesis is amyloid imaging biomarkers discovery, for which I propose an innovative machine learning paradigm enabling precision medicine in this domain. The paradigm tailors the imaging biomarker discovery process to individual characteristics of a given patient. I implement this paradigm using a newly developed learning-to-rank method PLTR. The PLTR model seamlessly integrates two objectives for joint optimization: pushing up relevant biomarkers and ranking among relevant biomarkers. The empirical study of PLTR conducted on the ADNI data yields promising results to identify and prioritize individual-specific amyloid imaging biomarkers based on the individual’s structural MRI data. The resulting top ranked imaging biomarkers have the potential to aid personalized diagnosis and disease subtyping

Improving protein docking with binding site prediction

Protein-protein and protein-ligand interactions are fundamental as many proteins mediate their biological function through these interactions. Many important applications follow directly from the identification of residues in the interfaces between protein-protein and protein-ligand interactions, such as drug design, protein mimetic engineering, elucidation of molecular pathways, and understanding of disease mechanisms. The identification of interface residues can also guide the docking process to build the structural model of protein-protein complexes. This dissertation focuses on developing computational approaches for protein-ligand and protein-protein binding site prediction and applying these predictions to improve protein-protein docking. First, we develop an automated approach LIGSITEcs to predict protein-ligand binding site, based on the notion of surface-solvent-surface events and the degree of conservation of the involved surface residues. We compare our algorithm to four other approaches, LIGSITE, CAST, PASS, and SURFNET, and evaluate all on a dataset of 48 unbound/bound structures and 210 bound-structures. LIGSITEcs performs slightly better than the other tools and achieves a success rate of 71% and 75%, respectively. Second, for protein-protein binding site, we develop metaPPI, a meta server for interface prediction. MetaPPI combines results from a number of tools, such as PPI_Pred, PPISP, PINUP, Promate, and SPPIDER, which predict enzyme-inhibitor interfaces with success rates of 23% to 55% and other interfaces with 10% to 28% on a benchmark dataset of 62 complexes. After refinement, metaPPI significantly improves prediction success rates to 70% for enzyme-inhibitor and 44% for other interfaces. Third, for protein-protein docking, we develop a FFT-based docking algorithm and system BDOCK, which includes specific scoring functions for specific types of complexes. BDOCK uses family-based residue interface propensities as a scoring function and obtains improvement factors of 4-30 for enzyme-inhibitor and 4-11 for antibody-antigen complexes in two specific SCOP families. Furthermore, the degrees of buriedness of surface residues are integrated into BDOCK, which improves the shape discriminator for enzyme-inhibitor complexes. The predicted interfaces from metaPPI are integrated as well, either during docking or after docking. The evaluation results show that reliable interface predictions improve the discrimination between near-native solutions and false positive. Finally, we propose an implicit method to deal with the flexibility of proteins by softening the surface, to improve docking for non enzyme-inhibitor complexes

Mining Data with Feature Interactions

abstract: Models using feature interactions have been applied successfully in many areas such as biomedical analysis, recommender systems. The popularity of using feature interactions mainly lies in (1) they are able to capture the nonlinearity of the data compared with linear effects and (2) they enjoy great interpretability. In this thesis, I propose a series of formulations using feature interactions for real world problems and develop efficient algorithms for solving them. Specifically, I first propose to directly solve the non-convex formulation of the weak hierarchical Lasso which imposes weak hierarchy on individual features and interactions but can only be approximately solved by a convex relaxation in existing studies. I further propose to use the non-convex weak hierarchical Lasso formulation for hypothesis testing on the interaction features with hierarchical assumptions. Secondly, I propose a type of bi-linear models that take advantage of interactions of features for drug discovery problems where specific drug-drug pairs or drug-disease pairs are of interest. These models are learned by maximizing the number of positive data pairs that rank above the average score of unlabeled data pairs. Then I generalize the method to the case of using the top-ranked unlabeled data pairs for representative construction and derive an efficient algorithm for the extended formulation. Last but not least, motivated by a special form of bi-linear models, I propose a framework that enables simultaneously subgrouping data points and building specific models on the subgroups for learning on massive and heterogeneous datasets. Experiments on synthetic and real datasets are conducted to demonstrate the effectiveness or efficiency of the proposed methods.Dissertation/ThesisDoctoral Dissertation Computer Science 201