Comparative in silico/in vitro analysis of pharmacokinetic profiles of BET inhibitors Scientific paper

Abstract

Pharmacokinetic limitations are a common cause of drug development failure, making early-stage profiling essential to mitigate financial risks and guide compound optimization. The computational tools capable of predicting pharmacokinetic properties offer a valuable resource for the prioritizing of candidates during early discovery phases. This study provides a comparative analysis of in silico and in vitro pharmacokinetic profiles of bromodomain and extraterminal domain (BET) inhibitors (BIs), focusing on sixteen (+)-JQ1-derived compounds we previously synthesized. Using ADMETlab 2.0 software, we predicted key absorption, distribution, metabolism, and excretion (ADME) parameters and compared them with experimentally determined data. Strong correlations were observed for plasma protein binding, whereas notable dis­crepancies were identified in permeability and clearance values. Additionally, the analysis underscores the role of CYP3A4 as a critical enzyme in the meta­bolism of several BIs. These findings demonstrate the utility of computational tools like ADMETlab 2.0 for early pharmacokinetic profiling while highlighting the need for validation and refinement of predictive models. This work provides valuable insights into the pharmacokinetics of BIs and supports the integration of computational and experimental approaches in drug discovery.