Abstract: Small molecules are indispensable to modern medical therapy. However, their use may lead to unintended, negative medical outcomes commonly referred to as adverse drug reactions (ADRs). These effects vary widely in mechanism, severity, and populations affected, making ADR prediction and identification important public health concerns. Current methods rely on clinical trials and postmarket surveillance programs to find novel ADRs; however, clinical trials are limited by small sample size, whereas postmarket surveillance methods may be biased and inherently leave patients at risk until sufficient clinical evidence has been gathered. Systems pharmacology, an emerging interdisciplinary field combining network and chemical biology, provides important tools to uncover and understand ADRs and may mitigate the drawbacks of traditional methods. In particular, network analysis allows researchers to integrate heterogeneous data sources and quantify the interactions between biological and chemical entities. Recent work in this area has combined chemical, biological, and large-scale observational health data to predict ADRs in both individual patients and global populations. In this review, we explore the rapid expansion of systems pharmacology in the study of ADRs. We enumerate the existing methods and strategies and illustrate progress in the field with a model framework that incorporates crucial data elements, such as diet and comorbidities, known to modulate ADR risk. Using this framework, we highlight avenues of research that may currently be underexplored, representing opportunities for future work.

Abstract: PURPOSE: Polymer-xerogel composite materials have been introduced to better optimize local anesthetics release kinetics for the pain management. In a previous study, it was shown that by adjusting various compositional and nano-structural properties of both inorganic xerogels and polymers, zero-order release kinetics over 7 days can be achieved in vitro. In this study, in vitro release properties are confirmed in vivo using a model that tests for actual functionality of the released local anesthetics. METHODS: Composite materials made with tyrosine-polyethylene glycol(PEG)-derived poly(ether carbonate) copolymers and silica-based sol-gel (xerogel) were synthesized. The in vivo release from the composite controlled release materials was demonstrated by local anesthetics delivery in a rat incisional pain model. RESULTS: The tactile allodynia resulting from incision was significantly attenuated in rats receiving drug-containing composites compared with the control and sham groups for the duration during which natural healing had not yet taken place. The concentration of drug (bupivacaine) in blood is dose dependent and maintained stable up to 120 h post-surgery, the longest time point measured. CONCLUSIONS: These in vivo studies show that polymer-xerogel composite materials with controlled release properties represent a promising class of controlled release materials for pain management.

Abstract: Understanding the genetic basis underlying individual responses to drug treatment is a fundamental task with implications to drug development and administration. Pharmacogenomics is the study of the genes that affect drug response. The study of pharmacogenomic associations between a drug and a gene that influences the interindividual drug response, which is only beginning, holds much promise and potential. Although relatively few pharmacogenomic associations between drugs and specific genes were mapped in humans, large systematic screens have been carried out in the yeast Saccharomyces cerevisiae, motivating the constructing of a projection method. We devised a novel approach for the prediction of pharmacogenomic associations in humans using genome-scale chemogenomic data from yeast. We validated our method using both cross-validation and comparison to known drug-gene associations extracted from multiple data sources, attaining high AUC scores. We show that our method outperforms a previous technique, as well as a similar method based on known human associations. Last, we analyze the predictions and demonstrate their biological relevance to understanding drug response.

Abstract: Small-molecule inhibitors of DNA repair pathways are being intensively investigated as primary and adjuvant chemotherapies. We report the discovery that cardiac glycosides, natural products in clinical use for the treatment of heart failure and atrial arrhythmia, are potent inhibitors of DNA double-strand break (DSB) repair. Our data suggest that cardiac glycosides interact with phosphorylated mediator of DNA damage checkpoint protein 1 (phospho-MDC1) or E3 ubiquitin-protein ligase ring finger protein 8 (RNF8), two factors involved in DSB repair, and inhibit the retention of p53 binding protein 1 (53BP1) at the site of DSBs. These observations provide an explanation for the anticancer activity of this class of compounds, which has remained poorly understood for decades, and provide guidance for their clinical applications. This discovery was enabled by the development of the first high-throughput unbiased cellular assay to identify new small-molecule inhibitors of DSB repair. Our assay is based on the fully automated, time-resolved quantification of phospho-SER139-H2AX (gammaH2AX) and 53BP1 foci, two factors involved in the DNA damage response network, in cells treated with small molecules and ionizing radiation (IR). This primary assay is supplemented by robust secondary assays that establish lead compound potencies and provide further insights into their mechanisms of action. Although the cardiac glycosides were identified in an evaluation of 2366 small molecules, the assay is envisioned to be adaptable to larger compound libraries. The assay is shown to be compatible with small-molecule DNA cleaving agents, such as bleomycin, neocarzinostatin chromophore, and lomaiviticin A, in place of IR.

Abstract: Photoacoustic Tomography (PAT) is a deep-tissue imaging modality, with potential clinical applications in the diagnosis of arthritis, cancer and other disease conditions. Here, we identified Clofazimine (CFZ), a red-pigmented dye and anti-inflammatory FDA-approved drug, as a macrophage-targeting photoacoustic (PA) imaging agent. Spectroscopic experiments revealed that CFZ and its various protonated forms yielded optimal PAT signals at wavelengths -450 to 540 nm. CFZ's macrophage-targeting chemical and structural forms were detected with PA microscopy at a high contrast-to-noise ratio (CNR > 22 dB) as well as with macroscopic imaging using synthetic gelatin phantoms. In vivo, natural and synthetic CFZ formulations also demonstrated significant anti-inflammatory activity. Finally, the injection of CFZ was monitored via a real-time ultrasound-photoacoustic (US-PA) dual imaging system in a live animal and clinically relevant human hand model. These results demonstrate an anti-inflammatory drug repurposing strategy, while identifying a new PA contrast agent with potential applications in the diagnosis and treatment of arthritis.

Abstract: BACKGROUND: Molecular structures can be represented as strings of special characters using SMILES. Since each molecule is represented as a string, the similarity between compounds can be computed using SMILES-based string similarity functions. Most previous studies on drug-target interaction prediction use 2D-based compound similarity kernels such as SIMCOMP. To the best of our knowledge, using SMILES-based similarity functions, which are computationally more efficient than the 2D-based kernels, has not been investigated for this task before. RESULTS: In this study, we adapt and evaluate various SMILES-based similarity methods for drug-target interaction prediction. In addition, inspired by the vector space model of Information Retrieval we propose cosine similarity based SMILES kernels that make use of the Term Frequency (TF) and Term Frequency-Inverse Document Frequency (TF-IDF) weighting approaches. We also investigate generating composite kernels by combining our best SMILES-based similarity functions with the SIMCOMP kernel. With this study, we provided a comparison of 13 different ligand similarity functions, each of which utilizes the SMILES string of molecule representation. Additionally, TF and TF-IDF based cosine similarity kernels are proposed. CONCLUSION: The more efficient SMILES-based similarity functions performed similarly to the more complex 2D-based SIMCOMP kernel in terms of AUC-ROC scores. The TF-IDF based cosine similarity obtained a better AUC-PR score than the SIMCOMP kernel on the GPCR benchmark data set. The composite kernel of TF-IDF based cosine similarity and SIMCOMP achieved the best AUC-PR scores for all data sets.

Abstract: Fatty acid synthase (FASN), the enzyme that catalyzes de novo synthesis of fatty acids, is expressed in many cancer types. Its potential as a therapeutic target is well recognized, but inhibitors of FASN have not yet been approved for cancer therapy. Orlistat (ORL), an FDA-approved lipase inhibitor, is also an effective inhibitor of FASN. However, ORL is extremely hydrophobic and has low systemic uptake after oral administration. Thus, new strategies are required to formulate ORL for cancer treatment as a FASN inhibitor. Here, we report the development of a nanoparticle (NP) formulation of ORL using amphiphilic bioconjugates that are derived from hyaluronic acid (HA), termed Nano-ORL. The NPs were loaded with up to 20 wt % weight of ORL at greater than 95% efficiency. The direct inhibition of the human recombinant thioesterase domain of FASN by ORL extracted from Nano-ORL was similar to that of stock ORL. Nano-ORL demonstrated a similar ability to inhibit cellular FASN activity when compared to free ORL, as demonstrated by analysis of (14)C-acetate incorporation into lipids. Nano-ORL treatment also disrupted mitochondrial function similarly to ORL by reducing adenosine triphosphate turnover in MDA-MB-231 and LNCaP cells. Nano-ORL demonstrated increased potency compared to ORL toward prostate and breast cancer cells. Nano-ORL decreased viability of human prostate and breast cancer cell lines to 55 and 57%, respectively, while free ORL decreased viability to 71 and 79% in the same cell lines. Moreover, Nano-ORL retained cytotoxic activity after a 24 h preincubation in aqueous conditions. Preincubation of ORL dramatically reduced the efficacy of ORL as indicated by high cell viability (>85%) in both breast and prostate cell lines. These data demonstrate that NP formulation of ORL using HA-derived polymers retains similar levels of FASN, lipid synthesis, and ATP turnover inhibition while significantly improving the cytotoxic activity against cancer cell lines.

Abstract: Organic anion transporting polypeptide (OATP) 1B1 mediates the hepatic uptake of many drugs including lipid-lowering statins. Decreased OATP1B1 transport activity is often associated with increased systemic exposure of statins and statin-induced myopathy. Antimalarial drug chloroquine (CQ) is also used for long-term treatment of rheumatoid arthritis and systemic lupus erythematosus. CQ is lysosomotropic and inhibits protein degradation in lysosomes. The current studies were designed to determine the effects of CQ on OATP1B1 protein degradation, OATP1B1-mediated transport in OATP1B1-overexpressing cell line, and statin uptake in human sandwich-cultured hepatocytes (SCH). Treatment with lysosome inhibitor CQ increased OATP1B1 total protein levels in HEK293-OATP1B1 cells and in human SCH as determined by OATP1B1 immunoblot. In HEK293-FLAG-tagged OATP1B1 stable cell line, co-immunofluorescence staining indicated that intracellular FLAG-OATP1B1 is colocalized with lysosomal associated membrane glycoprotein (LAMP)-2, a marker protein of late endosome/lysosome. Enlarged LAMP-2-positive vacuoles with FLAG-OATP1B1 protein retained inside were readily detected in CQ-treated cells, consistent with blocking lysosomal degradation of OATP1B1 by CQ. In HEK293-OATP1B1 cells, without pre-incubation, CQ concentrations up to 100 muM did not affect OATP1B1-mediated [(3)H]E217G accumulation. However, pre-incubation with CQ at clinically relevant concentration(s) significantly decreased [(3)H]E217G and [(3)H]pitavastatin accumulation in HEK293-OATP1B1 cells and [(3)H]pitavastatin accumulation in human SCH. CQ pretreatment (25 muM, 2 h) resulted in approximately 1.9-fold decrease in Vmax without affecting Km of OATP1B1-mediated [(3)H]E217G transport in HEK293-OATP1B1 cells. Pretreatment with monensin and bafilomycin A1, which also have lysosome inhibition activity, significantly decreased OATP1B1-mediated transport in HEK293-OATP1B1 cells. Pharmacoepidemiologic studies using data from the U.S. Food and Drug Administration Adverse Event Reporting System indicated that CQ plus pitavastatin, rosuvastatin, and pravastatin, which are minimally metabolized by the cytochrome P450 enzymes, led to higher myopathy risk than these statins alone. In summary, the present studies report novel findings that lysosome is involved in degradation of OATP1B1 protein and that pre-incubation with lysosomotropic drug CQ downregulates OATP1B1 transport activity. Our in vitro data in combination with pharmacoepidemiologic studies support that CQ has potential to cause OATP-mediated drug-drug interactions.

Abstract: Gui-Zhi-Shao-Yao-Zhi-Mu (GSZ) decoction is a Traditional Chinese Medicine (TCM) formula commonly used for the treatment of Rheumatoid Arthritis (RA). The therapeutic effect of GSZ for RA treatment is supported by our clinical retrospective study. To uncover the potential mechanism underlying GSZ formula, we identified 1,327 targets of 673 compounds from 9 herbs that involve in Fc epsilon RI signaling pathway and regulation of immunoglobulin production. Comparison between formula targets with 79 RA drug targets and 675 RA disease genes showed that formula targets covered 31.6% RA drug targets and 19.9% RA disease genes. Formula specific targets presented expression patterns highly similar to the disease genes and drug targets based on the expression profiles of RA samples. Investigation of 10 inferred gene clusters from expression profiles with a target association network revealed that formula specific targets directly or indirectly interacted with disease genes that were essential for immune related biological processes (e.g. inflammatory responses, treatment response of rheumatoid arthritis, etc.). Our result indicated that GSZ disrupted the RA disease dysfunction modules and restored homeostasis in the human body. The systemic approach to infer therapeutic mechanisms of GSZ for RA treatment provides a new insight in the understanding of this TCM formula.

Abstract: The application of metabolomics towards cancer research has led to a renewed appreciation of metabolism in cancer development and progression. It has also led to the discovery of metabolite cancer biomarkers and the identification of a number of novel cancer causing metabolites. The rapid growth of metabolomics in cancer research is also leading to challenges. In particular, with so many cancer-associate metabolites being identified, it is often difficult to keep track of which compounds are associated with which cancers. It is also challenging to track down information on the specific pathways that particular metabolites, drugs or drug metabolites may be affecting. Even more frustrating are the difficulties associated with identifying metabolites from NMR or MS spectra. Fortunately, a number of metabolomics databases are emerging that are designed to address these challenges. One such database is the Human Metabolome Database (HMDB). The HMDB is currently the world's largest and most comprehensive, organism-specific metabolomics database. It contains more than 40,000 metabolite entries, thousands of metabolite concentrations, >700 metabolic and disease-associated pathways, as well as information on dozens of cancer biomarkers. This review is intended to provide a brief summary of the HMDB and to offer some guidance on how it can be used in metabolomic studies of cancer.