Data Driven Computational Design and Experimental Validation of Drugs for Accelerated Mitigation of Pandemic-like Scenarios.

Emerging pathogens are a historic threat to public health and economic stability. Current trial-and-error approaches to identify new therapeutics are often ineffective due to their inefficient exploration of the enormous small molecule design space. Here, we present a data-driven computational framework composed of hybrid evolutionary algorithms for evolving functional groups on existing drugs to improve their binding affinity toward the main protease (Mpro) of SARS-CoV-2. We show that combinations of functional groups and sites are critical to design drugs with improved binding affinity, which can be easily achieved using our framework by exploring a fraction of the available search space. Atomistic simulations and experimental validation elucidate that enhanced and prolonged interactions between functionalized drugs and Mpro residues result in their improved therapeutic value over that of the parental compound. Overall, this novel framework is extremely flexible and has the potential to rapidly design inhibitors for any protein with available crystal structures.

The utility of collateral student drinking reports: Evidence from a biomarker study.

INTRODUCTION: Researchers have increasingly used collateral informants to validate the reports provided by primary research subjects. We assessed the utility of collateral informants for college students in a study that incorporates biomarkers to validate student reports of recent drinking behavior. METHODS: Students from a Midwestern university were randomly selected for a study in which they provided 90-day Timeline Followback data, hair and fingernail specimens for ethylglucuronide (EtG) testing, and information about collateral (friends or peers) informants who were familiar with their drinking behavior. We compared summary measures of recent drinking to collateral informant reports for the subset of 72 students who were selected to participate in the collateral validation process who had complete measures. Kappa, weighted kappa, and McNemar tests were performed to evaluate levels of agreement. We compared levels of use indicated by each informant within the context of EtG findings. We also compared respondent and collateral reports with respect to heavy drinking directly to EtG test results. RESULTS: There was considerable overlap between the reports provided by the student participants and their collateral informants. Within the context of EtG-informed analyses, collaterals rarely provided new information about heavy use beyond that provided by the study subjects. CONCLUSIONS: Collateral informants have limited utility in non-clinical studies of heavy drinking in randomly selected college students.

Detection of codeine, morphine, 6-monoacetylmorphine, and meconin in human umbilical cord tissue: method validation and evidence of in utero heroin exposure.

BACKGROUND: Heroin abuse is a significant public health issue and is on the rise because of the unintended consequences of strengthening controls for nonmedical use of prescription pain killers. Included in this trend is an increase in opiate exposed newborns that are particularly vulnerable to a number of negative health outcomes. METHODS: After presenting a fully validated liquid chromatography-tandem mass spectrometric method for codeine, morphine, 6-monoacetylmorphine, and meconin, a metabolite of the heroin contaminant noscapine, we compared the outcome of 46 authentic umbilical specimens with the results generated using a previous less sensitive method that did not include meconin. Additionally, we provided a summary of opiate finding from a year-long survey of specimens received into a commercial reference laboratory. RESULTS: The limits of detection for all 4 compounds were 0.1 ng/g, the limit of quantitation was 0.2 ng/g, and the assay was linear from 0.2 to 10.0 ng/g. Of the 46 comparative specimens, this method improved the identification of heroin exposure from 2 to 5, and the year-long survey identified 86 heroin-exposed newborns with 11 of them identified by the sole identification of meconin. CONCLUSIONS: This study demonstrated that a more sensitive analytical platform and the inclusion of meconin in the opiates assay improved the ability to distinguish between in utero heroin exposure and maternal administration of codeine or morphine.

Ethyl glucuronide in hair and fingernails as a long-term alcohol biomarker.

AIMS: This study aimed to evaluate the performance of ethyl glucuronide (EtG) in hair and fingernails as a long-term alcohol biomarker. DESIGN: Cross-sectional survey with probability sampling. SETTING: Midwestern United States. PARTICIPANTS: Participants were 606 undergraduate college students between the ages of 18 and 25 years at the time of selection for potential study participation. MEASUREMENTS: EtG concentrations in hair and fingernails were measured by liquid chromatography-tandem mass spectrometry at three thresholds [30 picograms (pg) per milligram (mg); 20 pg/mg; and 8 pg/mg]. Any weekly alcohol use, increasing-risk drinking and high-risk drinking on average during the past 12 weeks was assessed by participant interview using the time-line follow-back method. FINDINGS: In both hair and fingernails at all three EtG thresholds, sensitivity was greatest for the high-risk drinking group [hair: 0.43, confidence interval (CI)=0.17, 0.69 at 30 pg/mg, 0.71, CI=0.47, 0.95 at 20 pg/mg; 0.93, CI=0.79, 1.00 at 8 pg/mg; fingernails: 1.00, CI=1.00-1.00 at 30, 20 and 8 pg/mg] and specificity was greatest for any alcohol use (hair: 1.00, CI=1.00, 1.00 at 30 and 20 pg/mg; 0.97, CI=0.92-0.99 at 8 pg/mg; fingernails: 1.00, CI=1.00-1.00 at 30, 20 and 8 pg/mg). Areas under the receiver operating characteristic curves were significantly higher for EtG concentration in fingernails than hair for any weekly alcohol use (P = 0.02, DeLong test, two-tailed) and increasing-risk drinking (P = 0.02, DeLong test, two-tailed). CONCLUSIONS: Ethyl glucuronide, especially in fingernails, may have potential as a quantitative indicator of alcohol use.

Liquid Chromatography-Tandem Mass Spectrometry Assay to Detect Ethyl Glucuronide in Human Fingernail: Comparison to Hair and Gender Differences.

Over the past decade, the use of hair specimens for the long-term detection of the alcohol biomarker ethyl glucuronide has been increasing in popularity and usage. We evaluated the usefulness of fingernail clippings as a suitable alternative to hair for ethyl glucuronide detection. A liquid chromatography-tandem mass spectrometry method for the detection of ethyl glucuronide in fingernail clippings was fully validated and used to analyze the hair and/or fingernail specimens of 606 college-aged study participants. The limit of detection was 2 pg/mg, the limit of quantitation was 8 pg/mg and the method was linear from 8 to 2000 pg/mg. Intra- and inter-assay imprecision studies at three different concentrations (20, 40, 200 pg/mg) were all within 7.8% and all intra- and inter-assay bias studies at these levels were within 115.1% of target concentration. Ethyl glucuronide levels in fingernail (mean = 29.1 ± 55.6 pg/mg) were higher than ethyl glucuronide levels in hair (mean = 9.48 ± 22.3 pg/mg) and a correlation of the matched pairs was observed (r = 0.552, P < 0.01, n = 529). Evaluating each gender separately revealed that the correlation of male fingernail to male hair was large and significant (r = 0.782, P < 0.01, n = 195) while female hair to female fingernail was small yet significant (r = 0.249, P < 0.01, n = 334). The study results demonstrated that fingernail may be a suitable alternative to hair for ethyl glucuronide detection and may be the preferred sample type due to the lack of a gender bias.

Determination of amphetamine and methamphetamine in umbilical cord using liquid chromatography-tandem mass spectrometry.

The use of meconium as a drug-screening matrix for newborns has been the gold standard of care for the past two decades. A recent study using matched pairs of meconium and umbilical cord demonstrated a high degree of agreement. The use of liquid chromatography-tandem mass spectrometry as a means to confirm amphetamines presumptive positive umbilical cord specimens for amphetamine and methamphetamine is described here for the first time. The limit of detection for both compounds was 0.2 ng/g. The limit of quantitation for both compounds was 0.6 ng/g. The assay was linear for both compounds up to 100 ng/g.