The development and validation of a computational model to predict rat liver microsomal clearance

As the cost of discovering and developing new pharmaceutically relevant compounds continues to rise, it is increasingly important to select the right molecules to prosecute very early in drug discovery. The development of high throughput in vitro assays of hepatic metabolic clearance has allowed for vast quantities of data generation; however, these large screens are still costly and remain dependant on animal usage. To further expand the value of these screens and ultimately aid in animal usage reduction, we have developed an in silico model of rat liver microsomal (RLM) clearance. This model combines a large amount of rat clearance data (n = 27,697) generated at multiple Pfizer laboratories to represent the broadest possible chemistry space. The model predicts RLM stability (with 82% accuracy and a kappa value of 0.65 for test data set) based solely on chemical structural inputs, and provides a clear assessment of confidence in the prediction. The current in silico model should help accelerate the drug discovery process by using confidence-based stability-driven prioritization, and reduce cost by filtering out the most unstable/undesirable molecules. The model can also increase efficiency in the evaluation of chemical series by optimizing iterative testing and promoting rational drug design.