Current development of integrated web servers for preclinical safety and pharmacokinetics assessments in drug development

Abstract

Abstract 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/.