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In drug development, preclinical safety and pharmacokinetics assessments of candidate drugs to ensure the safety profile are a must. While in vivo and in vitro tests are traditionally used, experimental determinations have disadvantages, as they are usually time-consuming and costly. In silico predictions of these preclinical endpoints have each been developed in the past decades. However, only a few web-based tools have integrated different models to provide a simple one-step platform to help researchers thoroughly evaluate potential drug candidates. To efficiently achieve this approach, a platform for preclinical evaluation must not only predict key ADMET (absorption, distribution, metabolism, excretion and toxicity) properties but also provide some guidance on structural modifications to improve the undesired properties. In this review, we organized and compared several existing integrated web servers that can be adopted in preclinical drug development projects to evaluate the subject of interest. We also introduced our new web server, Virtual Rat, as an alternative choice to profile the properties of drug candidates. In Virtual Rat, we provide not only predictions of important ADMET properties but also possible reasons as to why the model made those structural predictions. Multiple models were implemented into Virtual Rat, including models for predicting human ether-a-go-go-related gene (hERG) inhibition, cytochrome P450 (CYP) inhibition, mutagenicity (Ames test), blood–brain barrier penetration, cytotoxicity and Caco-2 permeability. Virtual Rat is free and has been made publicly available at https://virtualrat.cmdm.tw/. [ABSTRACT FROM AUTHOR]

This study evaluated the effects of physically effective neutral detergent fiber (peNDF), and undigested neutral detergent fiber (uNDF) on dry matter intake (DMI), eating behavior, ruminal fermentation, and total tract permeability for finishing cattle. Simmental heifers (n=6; 667.8±28.4 kg) were used in a replicated 3×3 Latin square (21-d periods) balanced for carry-over effects. Barley grain-based diets were formulated to provide treatments with: low peNDF and low uNDF (95% barley and supplement, and 0% straw; 0FOR); low peNDF but high uNDF (85% barley and supplement, 10% pelleted straw; PEL); or high peNDF with high uNDF (85% barley and supplement, 10% chopped straw; ST). Treatment did not affect DMI (P=0.93). Heifers fed 0FOR spent less (P< 0.01) time eating vs. ST, where PEL was intermediate. Time spent ruminating was greater (P=0.01) for ST than 0FOR, with PEL not differing. Heifers fed 0FOR had fewer meals/d than ST (P< 0.01) and meal size was greater for 0FOR than PEL and ST (P< 0.01). Feeding 0FOR reduced (P=0.02) mean ruminal pH (5.65 vs. 6.07) and increased (522 vs. 288 min/d, P=0.02) the duration that pH was < 5.5 relative to ST with PEL being intermediate (5.82 and 504 min/d, respectively). Heifers fed 0FOR had greater (112.5 vs. 59.9 sec, P=0.05) time between contractions and lesser (61.45 vs. 94.58 mmHg'sec, P=0.05) contraction area compared with cattle fed ST, while PEL remained intermediate (76.73 sec and 73.29 mmHg×sec, respectively). Permeability of the gastrointestinal tract to Cr-EDTA and intestine to Co-EDTA did not differ (P=0.11) among treatments. The data suggest that increasing uNDF improved ruminal function, but increasing uNDF with peNDF is needed to decrease the risk of ruminal acidosis in finishing cattle. The results further suggest that the use of uNDF and peNDF may provide useful information over NDF inclusion when evaluating fiber adequacy of finishing diets. [ABSTRACT FROM AUTHOR]