Quantitative bioassay to identify antimicrobial drugs through drug interaction fingerprint analysis.
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ABSTRACT:
SUBMITTER: Weinstein ZB
PROVIDER: S-EPMC5311984 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDrug-drug interactions (DDIs) are responsible for many serious adverse events; their detection is crucial for patient safety but is very challenging. Currently, the US Food and Drug Administration and pharmaceutical companies are showing great interest in the development of improved tools for identifying DDIs.MethodsWe present a new methodology applicable on a large scale that identifies novel DDIs based on molecular structural similarity to drugs involved in established DDIs. The underlying assumption is that if drug A and drug B interact to produce a specific biological effect, then drugs similar to drug A (or drug B) are likely to interact with drug B (or drug A) to produce the same effect. DrugBank was used as a resource for collecting 9454 established DDIs. The structural similarity of all pairs of drugs in DrugBank was computed to identify DDI candidates.ResultsThe methodology was evaluated using as a gold standard the interactions retrieved from the initial DrugBank database. Results demonstrated an overall sensitivity of 0.68, specificity of 0.96, and precision of 0.26. Additionally, the methodology was also evaluated in an independent test using the Micromedex/Drugdex database.ConclusionThe proposed methodology is simple, efficient, allows the investigation of large numbers of drugs, and helps highlight the etiology of DDI. A database of 58 403 predicted DDIs with structural evidence is provided as an open resource for investigators seeking to analyze DDIs.
| S-EPMC3534468 | biostudies-literature
Project description:Quantitative prediction of cellular responses to drugs and drug combinations is a challenging and valuable topic in pharmaceutical research. In the past decade, microarray technology has become a routine tool for monitoring genome-wide expression changes and has been widely adopted for exploring drug response in the pharmaceutical field. However, how to predict the synergistic effect of drug combinations using microarray data is a challenging task. In this article, we report a simple prediction framework based on the genome-wide and quantitative profiling of cellular responses to individual drugs. By exploring the differential expression profiles, our correlation-based strategy can reveal the synergistic effects of drug combinations. The comparison with gold-standard experimental results demonstrates the strengths and weaknesses in relation to prediction based only on cellular response to individual drugs. Specifically, the prediction strategy may work for a drug combination whose individual drugs show related transcriptomic mechanisms but not for others.
| S-EPMC3944117 | biostudies-literature
Project description:BACKGROUND: Drug addiction is a complex and chronic mental disease, which places a large burden on the American healthcare system due to its negative effects on patients and their families. Recently, network pharmacology is emerging as a promising approach to drug discovery by integrating network biology and polypharmacology, allowing for a deeper understanding of molecular mechanisms of drug actions at the systems level. This study seeks to apply this approach for investigation of illicit drugs and their targets in order to elucidate their interaction patterns and potential secondary drugs that can aid future research and clinical care. RESULTS: In this study, we extracted 188 illicit substances and their related information from the DrugBank database. The data process revealed 86 illicit drugs targeting a total of 73 unique human genes, which forms an illicit drug-target network. Compared to the full drug-target network from DrugBank, illicit drugs and their target genes tend to cluster together and form four subnetworks, corresponding to four major medication categories: depressants, stimulants, analgesics, and steroids. External analysis of Anatomical Therapeutic Chemical (ATC) second sublevel classifications confirmed that the illicit drugs have neurological functions or act via mechanisms of stimulants, opioids, and steroids. To further explore other drugs potentially having associations with illicit drugs, we constructed an illicit-extended drug-target network by adding the drugs that have the same target(s) as illicit drugs to the illicit drug-target network. After analyzing the degree and betweenness of the network, we identified hubs and bridge nodes, which might play important roles in the development and treatment of drug addiction. Among them, 49 non-illicit drugs might have potential to be used to treat addiction or have addictive effects, including some results that are supported by previous studies. CONCLUSIONS: This study presents the first systematic review of the network characteristics of illicit drugs, their targets, and other drugs that share the targets of these illicit drugs. The results, though preliminary, provide some novel insights into the molecular mechanisms of drug addiction. The observation of illicit-related drugs, with partial verification from previous studies, demonstrated that the network-assisted approach is promising for the identification of drug repositioning.
| S-EPMC3849475 | biostudies-literature
Project description:Despite their high potential for drug-drug interactions (DDI), clinical DDI studies of antiretroviral drugs (ARVs) are often lacking, because the full range of potential interactions cannot feasibly or pragmatically be studied, with some high-risk DDI studies also being ethically difficult to undertake. Thus, a robust method to screen and to predict the likelihood of DDIs is required. We developed a method to predict DDIs based on two parameters: the degree of metabolism by specific enzymes, such as CYP3A, and the strength of an inhibitor or inducer. These parameters were derived from existing studies utilizing paradigm substrates, inducers, and inhibitors of CYP3A to assess the predictive performance of this method by verifying predicted magnitudes of changes in drug exposure against clinical DDI studies involving ARVs. The derived parameters were consistent with the FDA classification of sensitive CYP3A substrates and the strength of CYP3A inhibitors and inducers. Characterized DDI magnitudes (n = 68) between ARVs and comedications were successfully quantified, meaning 53%, 85%, and 98% of the predictions were within 1.25-fold (0.80 to 1.25), 1.5-fold (0.66 to 1.48), and 2-fold (0.66 to 1.94) of the observed clinical data. In addition, the method identifies CYP3A substrates likely to be highly or, conversely, minimally impacted by CYP3A inhibitors or inducers, thus categorizing the magnitude of DDIs. The developed effective and robust method has the potential to support a more rational identification of dose adjustment to overcome DDIs, being particularly relevant in an HIV setting, given the treatment's complexity, high DDI risk, and limited guidance on the management of DDIs.
| S-EPMC6021627 | biostudies-literature
Project description:COVID-19 is a global pandemic impacting the daily living of millions. As variants of the virus evolve, a complete comprehension of the disease and drug targets becomes a decisive duty. The Omicron variant, for example, has a notably high transmission rate verified in 155 countries. We performed integrative transcriptomic and network analyses to identify drug targets and diagnostic biomarkers and repurpose FDA-approved drugs for SARS-CoV-2. Upon the enrichment of 464 differentially expressed genes, pathways regulating the host cell cycle were significant. Regulatory and interaction networks featured hsa-mir-93-5p and hsa-mir-17-5p as blood biomarkers while hsa-mir-15b-5p as an antiviral agent. MYB, RRM2, ERG, CENPF, CIT, and TOP2A are potential drug targets for treatment. HMOX1 is suggested as a prognostic biomarker. Enhancing HMOX1 expression by neem plant extract might be a therapeutic alternative. We constructed a drug-gene network for FDA-approved drugs to be repurposed against the infection. The key drugs retrieved were members of anthracyclines, mitotic inhibitors, anti-tumor antibiotics, and CDK1 inhibitors. Additionally, hydroxyquinone and digitoxin are potent TOP2A inhibitors. Hydroxyurea, cytarabine, gemcitabine, sotalol, and amiodarone can also be redirected against COVID-19. The analysis enforced the repositioning of fluorouracil and doxorubicin, especially that they have multiple drug targets, hence less probability of resistance.
| S-EPMC9279364 | biostudies-literature
Project description:This paper reports the in vitro characterization of the interaction between the phosphate groups of DNA and the protonated species of drugs with basic groups through the determination of the affinity constants, the reversibility of the interaction, and the effect on the secondary structure of the macromolecule. Affinity constants of the counterionic condensation DNA-drug were in the order of 10?. The negative electrokinetic potential of DNA decreased with the increase of the proportion of loading drugs. The drugs were slowly released from the DNA-drug complexes and had release kinetics consistent with the high degree of counterionic condensation. The circular dichroism profile of DNA was not modified by complexation with atenolol, lidocaine, or timolol, but was significantly altered by the more lipophilic drugs benzydamine and propranolol, revealing modifications in the secondary structure of the DNA. The in vitro characterization of such interactions provides a physicochemical basis that would contribute to identify the effects of this kind of drugs in cellular cultures, as well as side effects observed under their clinical use. Moreover, this methodology could also be projected to the fields of intracellular DNA transfection and the use of DNA as a carrier of active drugs.
| S-EPMC5388140 | biostudies-literature
Project description:Different parts of Cnestis ferruginea are used in traditional African medicine for treating infectious diseases such as dysentery, bronchitis, eye troubles, conjunctivitis, sinusitis, gonorrhea, and syphilis. Despite its long traditional use in the treatment of infections, this plant is not well studied for its in vitro antimicrobial properties. Therefore, the present study aims to establish the antimicrobial activity profile of extracts from this plant, as well as to isolate and evaluate the antimicrobial activity of the most abundant bioactive compound in C. ferruginea leaves through bioassay-guided purification, using Staphylococcus aureus as a target organism. Although both methanol and water extracts of the plant leaves proved active against S. aureus, a water extract was pursued, and subjected further to liquid-liquid partitioning (ethyl acetate, butanol, and water). The ethyl acetate fraction was found to be the most potent and was subjected to silica gel chromatography. In total, 250 fractions were obtained, and those with similar TLC profiles were clustered into 22 major groups, of which pooled fraction-F6 (83 mg) was the most potent. Additional purification by HPLC resulted in two active peaks, which were identified, using a combination of NMR and mass spectrometry, as hydroquinone and caffeic acid methyl ester. Their antimicrobial activity was confirmed using a microdilution protocol on S. aureus, where hydroquinone had a stronger activity (MIC50 = 63 ?g/mL) compared to caffeic acid methyl ester (>200 ?g/mL). Traditionally this plant is used as an aqueous preparation to treat many infections, and the present study also demonstrated antimicrobial activity in the aqueous extract, which appears due mainly to two major water-soluble compounds isolated through bioassay-guided purification. This supports the clinical use of the aqueous extract of C. ferruginea leaves as a phytotherapeutic for bacterial infections.
| S-EPMC6470257 | biostudies-literature
Project description:The current convergence of molecular and pharmacological data provides unprecedented opportunities to gain insights into the relationships between the two types of data. Multiple forms of large-scale molecular data, including but not limited to gene and microRNA transcript expression, DNA somatic and germline variations from next-generation DNA and RNA sequencing, and DNA copy number from array comparative genomic hybridization are all potentially informative when one attempts to recognize the panoply of potentially influential events both for cancer progression and therapeutic outcome. Concurrently, there has also been a substantial expansion of the pharmacological data being accrued in a systematic fashion. For cancer cell lines, the National Cancer Institute cell line panel (NCI-60), the Cancer Cell Line Encyclopedia (CCLE), and the collaborative Genomics of Drug Sensitivity in Cancer (GDSC) databases all provide subsets of these forms of data. For the patient-derived data, The Cancer Genome Atlas (TCGA) provides analogous forms of genomic information along with treatment histories. Integration of these data in turn relies on the fields of statistics and statistical learning. Multiple algorithmic approaches may be chosen, depending on the data being considered, and the nature of the question being asked. Combining these algorithms with prior biological knowledge, the results of molecular biological studies, and the consideration of genes as pathways or functional groups provides both the challenge and the potential of the field. The ultimate goal is to provide a paradigm shift in the way that drugs are selected to provide a more targeted and efficacious outcome for the patient.
| S-EPMC4282979 | biostudies-literature
Project description:With substantial numbers of breast tumors showing or acquiring treatment resistance, it is of utmost importance to develop new agents for the treatment of the disease, to know their effectiveness against breast cancer and to understand their relationships with other drugs to best assign the right drug to the right patient. To achieve this goal drug screenings on breast cancer cell lines are a promising approach. In this study a large-scale drug screening of 37 compounds was performed on a panel of 42 breast cancer cell lines representing the main breast cancer subtypes. Clustering, correlation and pathway analyses were used for data analysis. We found that compounds with a related mechanism of action had correlated IC50 values and thus grouped together when the cell lines were hierarchically clustered based on IC50 values. In total we found six clusters of drugs of which five consisted of drugs with related mode of action and one cluster with two drugs not previously connected. In total, 25 correlated and four anti-correlated drug sensitivities were revealed of which only one drug, Sirolimus, showed significantly lower IC50 values in the luminal/ERBB2 breast cancer subtype. We found expected interactions but also discovered new relationships between drugs which might have implications for cancer treatment regimens.
| S-EPMC4628005 | biostudies-literature
Project description:Siji-kangbingdu mixture is an anti-inflammatory, anti-bacterial, and anti-viral herbal mixture which is frequently used by doctors to treat upper respiratory infections. It's important to establish an efficient and economical quality-control method to ensure the quality consistency and efficacy stability of Siji-kangbingdu mixture. In this study, an integrated multi-evaluation method was established, sequentially involving UPLC-TripleTOF-MS analysis, UPLC fingerprint analysis, and the quantitative analysis of multi-components using the single-marker (QAMS) method. With one chromatographic condition, a total of 71 compounds were identified by MS and MS/MS information, with a mass error of less than 5 ppm; 49 peaks detected in 254 nm were selected to establish the fingerprint similarity model, and 7 chemical compounds were simultaneously determined, namely, chlorogenic acid, liquiritin, rutin, isochlorogenic acid A, forsythin, forsythoside A, and glycyrrhizic acid, with forsythoside A as the reference standard. There was no significant difference in the content of the seven compounds between the QAMS method and the external standard method (ESM). The established multi-evaluation method will largely promote the quality control and standardization process of Siji-kangbingdu mixture. It also provides a reference workflow for the overall evaluation of TCM patent medicines, from chemical profiling to fingerprint and quantitative analysis.
| S-EPMC6804210 | biostudies-literature