Novel Development of Predictive Feature Fingerprints to Identify Chemistry-Based Features for the Effective Drug Design of SARS-CoV-2 Target Antagonists and Inhibitors Using Machine Learning.

A unique approach to bioactivity and chemical data curation coupled with random forest analyses has led to a series of target-specific and cross-validated predictive feature fingerprints (PFF) that have high predictability across multiple therapeutic targets and disease stages involved in the severe acute respiratory syndrome due to coronavirus 2 (SARS-CoV-2)-induced COVID-19 pandemic, which include plasma kallikrein, human immunodeficiency virus (HIV)-protease, nonstructural protein (NSP)5, NSP12, Janus kinase (JAK) family, and AT-1. The approach was highly accurate in determining the matched target for the different compound sets and suggests that the models could be used for virtual screening of target-specific compound libraries. The curation-modeling process was successfully applied to a SARS-CoV-2 phenotypic screen and could be used for predictive bioactivity estimation and prioritization for clinical trial selection; virtual screening of drug libraries for the repurposing of drug molecules; and analysis and direction of proprietary data sets.

Effect of itraconazole on the pharmacokinetics of rosuvastatin.

BACKGROUND: Rosuvastatin is a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Itraconazole, an inhibitor of cytochrome P450 (CYP) 3A4 and the transport protein P-glycoprotein, is known to interact with other HMG-CoA reductase inhibitors. The current trials aimed to examine in vivo the effect of itraconazole on the pharmacokinetics of rosuvastatin. METHODS: Two randomized, double-blind, placebo-controlled, 2-way crossover trials were performed. Healthy male volunteers (trial A, n = 12; trial B, n = 14) received itraconazole, 200 mg, or placebo once daily for 5 days; on day 4, 10 mg (trial A) or 80 mg (trial B) of rosuvastatin was coadministered. Plasma concentrations of rosuvastatin, rosuvastatin-lactone (trial A only), and active and total HMG-CoA reductase inhibitors were measured up to 96 hours after dosing. RESULTS: After coadministration with itraconazole, the rosuvastatin geometric least-square mean for the treatment ratio was increased by 39% for AUC(0-ct) (area under the rosuvastatin plasma concentration-time curve from time 0 to the last common time at which quantifiable concentrations were obtained for both treatments within a volunteer in trial A) and by 28% for AUC(0-t) (area under the rosuvastatin plasma concentration-time curve from time 0 to the time of the last quantifiable concentration in trial B), with the treatment ratio for maximum observed plasma drug concentration increased by 36% in trial A and 15% in trial B compared with placebo. For trial A (but not for trial B), the upper boundary of the 90% confidence interval for the treatment ratios fell outside the preset limits (0.7-1.43). The 95% confidence intervals for all treatment ratios (except maximum observed plasma drug concentration in trial B) did not include 1. These results indicate that itraconazole produces a modest increase in plasma concentrations of rosuvastatin. Rosuvastatin accounted for the majority of the circulating active HMG-CoA reductase inhibitors (> or =87%) and most of the total inhibitors (> or =75%). CONCLUSIONS: Itraconazole produced modest increases in rosuvastatin plasma concentrations, which are unlikely to be of clinical relevance. The results support previous in vitro metabolism findings that CYP3A4 plays a minor role in the limited metabolism of rosuvastatin.

Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects.

AIMS: To examine in vivo the effect of ketoconazole on the pharmacokinetics of rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. METHODS: This was a randomized, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers (n = 14) received ketoconazole 200 mg or placebo twice daily for 7 days, and rosuvastatin 80 mg was coadministered on day 4 of dosing. Plasma concentrations of rosuvastatin, and active and total HMG-CoA reductase inhibitors were measured up to 96 h postdose. RESULTS: Following coadministration with ketoconazole, rosuvastatin geometric least square mean AUC(0,t) and Cmax were unchanged compared with placebo (treatment ratios (90% confidence intervals): 1.016 (0.839, 1.230), 0.954 (0.722, 1.260), respectively). Rosuvastatin accounted for essentially all of the circulating active HMG-CoA reductase inhibitors and most (> 85%) of the total inhibitors. Ketoconazole did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. CONCLUSIONS: Ketoconazole did not produce any change in rosuvastatin pharmacokinetics in healthy subjects. The data suggest that neither cytochrome P450 3A4 nor P-gp-mediated transport contributes to the elimination of rosuvastatin.