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A printable hydrogel microarray for drug screening avoids false positives associated with promiscuous aggregating inhibitors.

ABSTRACT: A significant problem in high-throughput drug screening is the disproportionate number of false hits associated with drug candidates that form colloidal aggregates. Such molecules, referred to as promiscuous inhibitors, nonspecifically inhibit multiple enzymes and are thus not useful as potential drugs. Here, we report a printable hydrogel-based drug-screening platform capable of non-ambiguously differentiating true enzyme inhibitors from promiscuous aggregating inhibitors, critical for accelerating the drug discovery process. The printed hydrogels can both immobilize as well as support the activity of entrapped enzymes against drying or treatment with a protease or chemical denaturant. Furthermore, the printed hydrogel can be applied in a high-throughput microarray-based screening platform (consistent with current practice) to rapidly (?<25?min) and inexpensively identify only clinically promising lead compounds with true inhibitory potential as well as to accurately quantify the dose-response relationships of those inhibitors, all while using 95% less sample than required for a solution assay.

SUBMITTER: Mateen R

PROVIDER: S-EPMC5807445 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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A printable hydrogel microarray for drug screening avoids false positives associated with promiscuous aggregating inhibitors.

Mateen Rabia R Ali M Monsur MM Hoare Todd T

Nature communications 20180209 1

A significant problem in high-throughput drug screening is the disproportionate number of false hits associated with drug candidates that form colloidal aggregates. Such molecules, referred to as promiscuous inhibitors, nonspecifically inhibit multiple enzymes and are thus not useful as potential drugs. Here, we report a printable hydrogel-based drug-screening platform capable of non-ambiguously differentiating true enzyme inhibitors from promiscuous aggregating inhibitors, critical for accelera ...[more]

PMID: 29426913

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Project description:BackgroundA large number of probabilistic models used in sequence analysis assign non-zero probability values to most input sequences. To decide when a given probability is sufficient the most common way is bayesian binary classification, where the probability of the model characterizing the sequence family of interest is compared to that of an alternative probability model. We can use as alternative model a null model. This is the scoring technique used by sequence analysis tools such as HMMER, SAM and INFERNAL. The most prevalent null models are position-independent residue distributions that include: the uniform distribution, genomic distribution, family-specific distribution and the target sequence distribution. This paper presents a study to evaluate the impact of the choice of a null model in the final result of classifications. In particular, we are interested in minimizing the number of false predictions in a classification. This is a crucial issue to reduce costs of biological validation.ResultsFor all the tests, the target null model presented the lowest number of false positives, when using random sequences as a test. The study was performed in DNA sequences using GC content as the measure of content bias, but the results should be valid also for protein sequences. To broaden the application of the results, the study was performed using randomly generated sequences. Previous studies were performed on aminoacid sequences, using only one probabilistic model (HMM) and on a specific benchmark, and lack more general conclusions about the performance of null models. Finally, a benchmark test with P. falciparum confirmed these results.ConclusionsOf the evaluated models the best suited for classification are the uniform model and the target model. However, the use of the uniform model presents a GC bias that can cause more false positives for candidate sequences with extreme compositional bias, a characteristic not described in previous studies. In these cases the target model is more dependable for biological validation due to its higher specificity.

Project description:OBJECTIVES:Lung cancer CT screening can reduce lung cancer mortality, but high false-positive rates may cause adverse psychosocial consequences. The aim was to analyse the psychosocial consequences of false-positive lung cancer CT screening using the lung cancer screening-specific questionnaire, Consequences of Screening in Lung Cancer (COS-LC). DESIGN AND SETTING:This study was a matched cohort study, nested in the randomised Danish Lung Cancer Screening Trial (DLCST). PARTICIPANTS:Our study included all 130 participants in the DLCST with positive CT results in screening rounds 2-5, who had completed the COS-LC questionnaire. Participants were split into a true-positive and a false-positive group and were then matched 1:2 with a control group (n=248) on sex, age (±3 years) and the time of screening for the positive CT groups or clinic visit for the control group. The true positives and false positives were also matched 1:2 with participants with negative CT screening results (n=252). PRIMARY OUTCOMES:Primary outcomes were psychosocial consequences measured at five time points. RESULTS:False positives experienced significantly more negative psychosocial consequences in seven outcomes at 1 week and in three outcomes at 1 month compared with the control group and the true-negative group (mean ? score >0 and p<0.001). True positives experienced significantly more negative psychosocial consequences in one outcome at 1 week (mean ? score 2.86 (95% CI 1.01 to 4.70), p=0.0024) and in five outcomes at 1 month (mean ? score >0 and p<0.004) compared with the true-negative group and the control group. No long-term psychosocial consequences were identified either in false positives or true positives. CONCLUSIONS:Receiving a false-positive result in lung cancer screening was associated with negative short-term psychosocial consequences. These findings contribute to the evidence on harms of screening and should be taken into account when considering implementation of lung cancer screening programmes. TRIAL REGISTRATION NUMBER:NCT00496977.

Dataset Information

A printable hydrogel microarray for drug screening avoids false positives associated with promiscuous aggregating inhibitors.

Publications

A printable hydrogel microarray for drug screening avoids false positives associated with promiscuous aggregating inhibitors.

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