Identifying Compound-Target Associations by Combining Bioactivity Profile Similarity Search and Public Databases Mining

Molecular target identification is of central importance to drug discovery. Here, we developed a computational approach, named bioactivity profile similarity search (BASS), for associating targets to small molecules by using the known target annotations of related compounds from public databases. To evaluate BASS, a bioactivity profile database was constructed using 4296 compounds that were commonly tested in the US National Cancer Institute 60 human tumor cell line anticancer drug screen (NCI-60). Each compound was used as a query to search against the entire bioactivity profile database, and reference compounds with similar bioactivity profiles above a threshold of 0.75 were considered as neighbor compounds of the query. Potential targets were subsequently linked to the identified neighbor compounds by using the known targets o

A Network-Based Multi-Target Computational Estimation Scheme for Anticoagulant Activities of Compounds

BACKGROUND: Traditional virtual screening method pays more attention on predicted binding affinity between drug molecule and target related to a certain disease instead of phenotypic data of drug molecule against disease system, as is often less effective on discovery of the drug which is used to treat many types of complex diseases. Virtual screening against a complex disease by general network estimation has become feasible with the development of network biology and system biology. More effective methods of computational estimation for the whole efficacy of a compound in a complex disease system are needed, given the distinct weightiness of the different target in a biological process and the standpoint that partial inhibition of several targets can be more efficient than the complete inhibition of a single target. METHODOLOGY: We developed a novel approach by integrating the affinity predictions from multi-target docking studies with biological network efficiency analysis to estimate the anticoagulant activities of compounds. From results of network efficiency calculation for human clotting cascade, factor Xa and thrombin were identified as the two most fragile enzymes, while the catalytic reaction mediated by complex IXa:VIIIa and the formation of the complex VIIIa:IXa were recognized as the two most fragile biological matter in the human clotting cascade system. Furthermore, the method which combined network efficiency with molecular docking scores was applied to estimate the anticoagulant activities of a serial of argatroban intermediates and eight natural products respectively. The better correlation (r = 0.671) between the experimental data and the decrease of the network deficiency suggests that the approach could be a promising computational systems biology tool to aid identification of anticoagulant activities of compounds in drug discovery. CONCLUSIONS: This article proposes a network-based multi-target computational estimation method for anticoagulant activities of compounds by combining network efficiency analysis with scoring function from molecular docking

The Synergistic Effect of Concomitant Schistosomiasis, Hookworm, and Trichuris Infections on Children's Anemia Burden

Polyparasitic infections have been recognized as the norm in many tropical developing countries, but the significance of this phenomenon for helminth-associated morbidities is largely unexplored. Earlier studies have suggested that multi-species, low-intensity parasitic infections were associated with higher odds of anemia among school-age children relative to their uninfected counterparts or those with one low-intensity infection. However, specific studies of the nature of interactions between helminth species in the mediation of helminth-associated morbidities are lacking. This study quantifies the extent to which polyparasitic infections have more than the sum of adverse effects associated with individual infections in the context of childhood anemia. This study found that the risk of anemia is amplified beyond the sum of risks for individual infections in children simultaneously exposed to 1) hookworm and schistosomiasis, and 2) hookworm and trichuris, and suggests that combined treatment for some geohelminth species and schistosomiasis could yield greater than additive benefits for the reduction of childhood anemia in helminth-endemic areas. However, more studies to understand the full range of interactions between parasitic species in their joint effects on helminth-associated morbidities will be necessary to better predict the impact of any future public health intervention

Treatment of Community-Acquired Pneumonia in Immunocompromised Adults:A Consensus Statement Regarding Initial Strategies

Background Community-acquired pneumonia (CAP) guidelines have improved the treatment and outcomes of patients with CAP, primarily by standardization of initial empirical therapy. But current society-published guidelines exclude immunocompromised patients. Research Question There is no consensus regarding the initial treatment of immunocompromised patients with suspected CAP. Study Design and Methods This consensus document was created by a multidisciplinary panel of 45 physicians with experience in the treatment of CAP in immunocompromised patients. The Delphi survey methodology was used to reach consensus. Results The panel focused on 21 questions addressing initial management strategies. The panel achieved consensus in defining the population, site of care, likely pathogens, microbiologic workup, general principles of empirical therapy, and empirical therapy for specific pathogens. Interpretation This document offers general suggestions for the initial treatment of the immunocompromised patient who arrives at the hospital with pneumonia

Airway epithelial transcription factor NK2 homeobox 1 inhibits mucous cell metaplasia and Th2 inflammation

Rationale: Airway mucous cell metaplasia and chronic inflammation are pathophysiological features that influence morbidity and mortality associated with asthma and other chronic pulmonary disorders. Elucidation of the molecular mechanisms regulating mucous metaplasia and hypersecretion provides the scientific basis for diagnostic and therapeutic opportunities to improve the care of chronic pulmonary diseases. Objectives: To determine the role of the airway epithelial–specific transcription factor NK2 homeobox 1 (NKX2-1, also known as thyroid transcription factor-1 [TTF-1]) in mucous cell metaplasia and lung inflammation. Methods: Expression of NKX2-1 in airway epithelial cells from patients with asthma was analyzed. NKX2-1+/? gene targeted or transgenic mice expressing NKX2-1 in conducting airway epithelial cells were sensitized to the aeroallergen ovalbumin. In vitro studies were used to identify mechanisms by which NKX2-1 regulates mucous cell metaplasia and inflammation. Measurements and Main Results: NKX2-1 was suppressed in airway epithelial cells from patients with asthma. Reduced expression of NKX2-1 in heterozygous NKX2-1+/? gene targeted mice increased mucous metaplasia in the small airways after pulmonary sensitization to ovalbumin. Conversely, mucous cell metaplasia induced by aeroallergen was inhibited by expression of NKX2-1 in the respiratory epithelium in vivo. Genome-wide mRNA analysis of lung tissue from ovalbumin-treated mice demonstrated that NKX2-1 inhibited mRNAs associated with mucous metaplasia and Th2-regulated inflammation, including Spdef, Ccl17, and Il13. In vitro, NKX2-1 inhibited SPDEF, a critical regulator of airway mucous cell metaplasia, and the Th2 chemokine CCL26. Conclusions: The present data demonstrate a novel function for NKX2-1 in a gene network regulating mucous cell metaplasia and allergic inflammation in the respiratory epithelium