An in silico study of the ligand binding to human cytochrome P450
Creators: name: Mo, Suilin
Publisher: name: RMIT University
Year: 2024

description: Cytochrome P450 (CYP) 2D6 can metabolize about 25% of clinical drugs and is subject to inhibition and polymorphism with significant clinical consequences. The elucidation of its crystal structure has provided very useful information on molecular interaction, specificity, and selectivity. However, the resolved structure of CYP2D6 is ligand-free, and thus how and whether ligand binding induces conformational changes of the active site is unknown. The molecular factors affecting the binding of compounds to CYP2D6 are also not fully elucidated. Herbal medicines may result in potential adverse herb-drug interactions when used in combination with conventional drugs. But, because of their complicated chemical composition and limited in vivo and in vitro approaches, there are limited data on the binding affinities and binding mechanisms of herbal compounds with CYP2D6.<br><br>In this regard, we hypothesize that a number of physicochemical factors determine the binding of compounds to human CYP2D6, and that a number of compounds share similar structural features, and therefore binding features as CYP2D6 substrates/inhibitors. Thus, the objectives of the current project are: (1) to further explore the molecular factors determining the binding of a compound to native and mutated CYP2D6; (2) to develop a QSAR model for the prediction of binding strength of compounds to CYP2D6; and (3) to examine the binding of Chinese herbal compounds from S. baicalensis/Fangjifuling decoction with CYP2D6.<br><br>In this study, we have developed and validated pharmacophore models for the CYP2D6 substrates/inhibitors. The models all consisted of two hydrophobic features and one hydrogen bond acceptor feature, with a relevance ratio of 76% for substrates and 78.8% for inhibitors. QSAR models for the prediction of binding affinity of ligands to CYP2D6 were also have been constructed and validated (y=0.980x+2.829 for substrates and y=0.948x+1.051 for inhibitors). In docking study, 117 out of 120 substrates and 30 out of 33 inhibitors could be docked into the active site of CYP2D6. Eleven residues for substrates and 8 residues for inhibitors presented an important role in their binding and consequently determining the metabolic activity towards the substrate/inhibitor selectivity. Apparent changes of the binding modes have been observed with Phe120Ile, Glu216Asp, Asp301Glu mutations, when five probe substrates and four known inhibitors were be tested. Eighteen out of 40 compounds from S. baicalensis and 60 out of 130 compounds from Fangjifuling decoction were mapped with our optimized pharmacophore models. Among them, 100% compounds from S. baicalensis and 90% from Fangjifuling decoction could be docked into the active site, which suggested that they may be substrates/inhibitors of CYP2D6. The role of Phe120, Glu216, Asp301, Ser304 for herbal compound binding to CYP2D6 has been further supported by our docking studies.<br><br>In conclusion, our project has documented the main molecular factors determining the binding of a compound to native and mutated CYP2D6, which allow us to predict and understand the interaction between molecules and CYP2D6. We also have demonstrated the use of an effective and efficient computational approach to studying the molecular mechanisms of interaction of herbal compounds and functionally important proteins.