In silico approach for drug-drug interaction

Enzyme induction

Abstract

Recently, many guidances about drug development and applications have been published by authorities in Japan, USA, and EU. The guidance published in 2012 by FDA attracts industrial attentions so much. The experimental methods and evaluations for DDIs in detail, for example CYP inhibition and induction, are described there. Then, the pharmaceutical company researchers should not only obey with this guidance but also try to avoid DDI beforehand prior to drug development stage. Here, we summarize the problems to be cleared in DDI, and the method for the prediction of DDI using molecular informatics. Then, we shows 3D-QSAR model for pregnane X receptor (PXR) as an example. The PXR that induces the expression of xenobiotic metabolism and transporter genes such as cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) is a nuclear receptor activated by agonists. Novel drug candidates that are PXR agonists may cause severe DDI and should be eliminated from the drug discovery process. In this study, we used MD simulation, MM-GB/SA, and CoMFA to predict the potency of drug induction by PXR quantitatively.