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Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects.

ABSTRACT: BACKGROUND:Promiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread. Such unintended interactions can be exploited to suggest drug repurposing possibilities as well as to identify potential molecular mechanisms responsible for observed side-effects. METHODS:We perform a large-scale analysis to detect binding-site molecular interaction field similarities between the binding-sites of the primary target of 400 drugs against a dataset of 14082 cavities within 7895 different proteins representing a non-redundant dataset of all proteins with known structure. Statistically-significant cases with high levels of similarities represent potential cases where the drugs that bind the original target may in principle bind the suggested off-target. Such cases are further analysed with docking simulations to verify if indeed the drug could, in principle, bind the off-target. Diverse sources of data are integrated to associated potential cross-reactivity targets with side-effects. RESULTS:We observe that promiscuous binding-sites tend to display higher levels of hydrophobic and aromatic similarities. Focusing on the most statistically significant similarities (Z-score???3.0) and corroborating docking results (RMSD?

SUBMITTER: Chartier M

PROVIDER: S-EPMC5408384 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects.

Chartier Matthieu M Morency Louis-Philippe LP Zylber María Inés MI Najmanovich Rafael J RJ

BMC pharmacology & toxicology 20170428 1

<h4>Background</h4>Promiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread. Such unintended interactions can be exploited to suggest drug repurposing possibilities as well as to identify potential molecular mechanisms responsible for observed side-effects.<h4>Methods</h4>We perform a large-scale analysis to detect binding-site molecular interaction field similarities between the binding-sites of the primary target of 400 drugs against a dataset ...[more]

PMID: 28449705

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Project description:BackgroundAntidepressants are known to show heterogeneous effects across individuals and conditions, posing challenges to understanding their efficacy in mental health treatment. Social media platforms enable individuals to share their day-to-day concerns with others and thereby can function as unobtrusive, large-scale, and naturalistic data sources to study the longitudinal behavior of individuals taking antidepressants.ObjectiveWe aim to understand the side effects of antidepressants from naturalistic expressions of individuals on social media.MethodsOn a large-scale Twitter data set of individuals who self-reported using antidepressants, a quasi-experimental study using unsupervised language analysis was conducted to extract keywords that distinguish individuals who improved and who did not improve following the use of antidepressants. The net data set consists of over 8 million Twitter posts made by over 300,000 users in a 4-year period between January 1, 2014, and February 15, 2018.ResultsFive major side effects of antidepressants were studied: sleep, weight, eating, pain, and sexual issues. Social media language revealed keywords related to these side effects. In particular, antidepressants were found to show a spectrum of effects from decrease to increase in each of these side effects.ConclusionsThis work enhances the understanding of the side effects of antidepressants by identifying distinct linguistic markers in the longitudinal social media data of individuals showing the most and least improvement following the self-reported intake of antidepressants. One implication of this work concerns the potential of social media data as an effective means to support digital pharmacovigilance and digital therapeutics. These results can inform clinicians in tailoring their discussion and assessment of side effects and inform patients about what to potentially expect and what may or may not be within the realm of normal aftereffects of antidepressants.

Dataset Information

Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects.

Publications

Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects.

Similar Datasets

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