Abstract
Human oral bioavailability (HOB) is a key factor in determining the fate of new drugs in clinical trials. HOB is conventionally measured using expensive and time-consuming experimental tests. The use of computational models to evaluate HOB before the synthesis of new drugs will be beneficial to the drug development process. In this study, a total of 1588 drug molecules with HOB data were collected from the literature for the development of a classifying model that uses the consensus predictions of five random forest models. The consensus model shows excellent prediction accuracies on two independent test sets with two cutoffs of 20% and 50% for classification of molecules. The analysis of the importance of the input variables allowed the identification of the main molecular descriptors that affect the HOB class value. The model is available as a web server at www.icdrug.com/ICDrug/ADMET for quick assessment of oral bioavailability for small molecules. The results from this study provide an accurate and easy-to-use tool for screening of drug candidates based on HOB, which may be used to reduce the risk of failure in late stage of drug development.Graphical
Highlights
Poor pharmacokinetic properties, including absorption, distribution, metabolism, excretion, and toxicity (ADMET), are the key reasons of late-stage failures in drug development [1]
The accurate prediction of these properties is becoming increasingly important in drug discovery
The results suggest that the chemical space of the two test sets is roughly within the space of the training set, it is sensible to use the prediction model trained by the training set to predict the Human oral bioavailability (HOB) values for the test sets
Summary
Poor pharmacokinetic properties, including absorption, distribution, metabolism, excretion, and toxicity (ADMET), are the key reasons of late-stage failures in drug development [1]. Among the ADMET properties, one of the most important pharmacokinetic characteristics of newly developed drugs is high oral bioavailability. Human oral bioavailability (HOB) is an important pharmacokinetic parameter that measures the amount of a drug that enters circulation within the body after ingestion. If intravenous administration is used, the human body can use the blood to deliver the drug to the site where it can exert pharmacological effects through the systemic circulation. Higher oral availability of the drug can reduce the amount of administration required to achieve the expected pharmacological effect because it can reduce the side effects and toxicity risks brought by the drug. The level of oral availability is one of the key factors determining the success or failure of clinical trials of new drugs
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