Computational Prediction of the Site(s) of Metabolism and Binding Modes of Protein Kinase Inhibitors Metabolized by CYP3A4

Nair, Pramod C.; Miners, John O.

doi:10.1124/dmd.118.085167

Cited by 15 publications

(18 citation statements)

References 84 publications

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“…It is intriguing that none of the prior computational studies identified Thr224 as residue that could facilitate the ligand association to CYP3A4 [ 17 , 20 , 22 , 23 , 24 , 25 , 26 , 27 ]. The CYP3A4–fluorol complex is the fourth structure where the ligand binding mode is stabilized via direct H-bonding to Thr224 [ 5 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of CYP3A4 Complexed with Fluorol Identifies the Substrate Access Channel as a High-Affinity Ligand Binding Site

Sevrioukova

2022

IJMS

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Cytochrome P450 3A4 (CYP3A4) is a major human drug-metabolizing enzyme, notoriously known for its extreme substrate promiscuity, allosteric behavior, and implications in drug–drug interactions. Despite extensive investigations, the mechanism of ligand binding to CYP3A4 is not fully understood. We determined the crystal structure of CYP3A4 complexed with fluorol, a small fluorescent dye that can undergo hydroxylation. In the structure, fluorol associates to the substrate channel, well suited for the binding of planar polyaromatic molecules bearing polar groups, through which stabilizing H-bonds with the polar channel residues, such as Thr224 and Arg372, can be established. Mutagenesis, spectral, kinetic, and functional data confirmed the involvement but not strict requirement of Thr224 for the association of fluorol. Collectively, our data identify the substrate channel as a high-affinity ligand binding site and support the notion that hydrophobic ligands first dock to the nearby peripheral surface, before migrating to the channel and, subsequently, into the active site.

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Section: Discussionmentioning

confidence: 99%

Crystal Structure of CYP3A4 Complexed with Fluorol Identifies the Substrate Access Channel as a High-Affinity Ligand Binding Site

Sevrioukova

2022

IJMS

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“…The molecular docking experiment was conducted using a slightly modified protein crystal structure of CYP3A4 complexed with ketoconazole (PDB ID: 2V0M) [8][9]. The ligands used in this investigation were four major compounds from C. asiatica and three known compounds from O. stamineus as reported in previous literature [10][11][12].…”

Section: Methodsmentioning

confidence: 99%

Site of Metabolism (SOM) Predictions for Centella asiatica and Orthosiphon stamineus Marker Compounds with CYP3A4 Using a Molecular Docking Approach

Ridhwan

2021

MJCHEM

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The human liver enzyme CYP3A4 plays an important role in the biotransformation of xenobiotics from herbs to harmless and excretable metabolites. However, CYP3A4 catalytic activity may also produce more toxic metabolites. Predicting sites of metabolism (SOMs) in the xenobiotics may prevent unwanted CYP3A4 products. The evidence to explain the comprehensive biotransformation of major compounds from Centella asiatica and Orthosiphon stamineus is inadequate. The aim of the present study was to determine the specific interaction between CYP3A4 ferric-oxidative active sites and potential SOMs for the major chemical compounds of C. asiatica and O. stamineus. Molecular docking on CYP3A4 ferric-oxo (bound to the protoporphirin group, HEME-Fe 3+ -O -) was carried out using the CDOCKER simulation program to predict the SOMs for compounds from C. asiatica (asiaticoside, madecassoside, asiatic acid and madecassic acid) and O. stamineus (sinensetin, eupatorin and 5-hydroxy-6,7,3',4'-tetramethoxyflavone (5TMF)). Binding energies, residue-ligand interactions, and SOMs were obtained from the analysis. The molecular docking results also revealed that sinensetin, eupatorin, and 5TMF bound strongly to the CYP3A4 active site with binding energies of -22.44, -34.29, and -25.84 kcal/mol, respectively. Generally, the residues Arg106, Ile301, Ther309, Glu374 and Ala307 were identified to have the highest number of interactions with eupatorine, 5TMF and sinensetin. The SOM prediction for eupatorine showed interactions between the oxygen of the HEME iron (ferric-oxo) and the C-11 and O-4 atoms. The possible metabolism reactions were C-11-hydroxylation and O-4-demethylation. For 5TMF, the SOM prediction for interactions were at the C-13 and O-7 positions, which could undergo hydroxylation and O-demethylation reactions, respectively. The SOM of sinensetin was predicted at C-3' and the possible metabolic reaction taking place would be hydroxylation. The present study concluded that the major compounds of O. stamineus have the potential to be metabolized by CYP3A4 through hydroxylation and O-demethylation reactions. These data may be useful for phytomedicine product development related to CYP3A4 biotransformation mechanisms.

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“…Molecular docking experiments were conducted using the Surflex-Dock docking suite (31) as previously reported (11,32). The resulting binding poses were ranked according to the total score (SYBYL Surflex-Dock).…”

Section: Computational Studies Of the Docking Of Sor And Sno Into The Active Sites Of Cyp2c8 And Cyp2c9mentioning

confidence: 99%

Differential inhibition of human CYP2C8 and molecular docking interactions elicited by sorafenib and its major N-oxide metabolite

Nair

Gillani

Rawling

et al. 2021

Chemico-Biological Interactions

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The multikinase inhibitor sorafenib (SOR) is a frontline agent in the treatment of hepatocellular and renal cancers. In recent clinical studies SOR has been evaluated increasingly in combination with other oncology agents, such as paclitaxel. However, the use of such combinations could increase the likelihood of pharmacokinetic drug-drug interactions (DDIs) and adverse events. It has been reported that SOR may inhibit a number of human drug oxidation pathways mediated by multiple CYPs. Oxidative biotransformation of SOR generates the pharmacologically active N-oxide metabolite (SNO) that has been shown to accumulate in the serum of some individuals who have been treated with the drug. Recent evidence has suggested that the metabolite SNO is more effective than the parent drug as an inhibitor of some CYP-mediated drug oxidations. Molecular docking studies have shown that SNO is associated with an increase in the binding interactions with active site amino acid residues in these enzymes. SOR has been implicated as an inhibitor of CYP2C8, which is an important catalyst in the oxidative elimination of oncology drugs such as paclitaxel and imatinib; inhibition is potentiated by NADPH-dependent biotransformation of SOR. The present study evaluated the potential contribution of SNO to the inhibition of CYP2C8 and the closely related enzyme CYP2C9. The principal finding to emerge was that SNO was ~2fold more effective than SOR as an inhibitor of CYP2C8-mediated paclitaxel 6hydroxylation in human liver. Both SOR and SNO interacted with active site residues in the catalytic center of CYP2C8; there were four additional hydrogen and halogen bonding interactions involving SNO. In contrast, the binding of SOR and SNO in the active site of CYP2C9 and the capacity to inhibit microsomal losartan oxidation were similar. These findings suggest that SNO has the potential to contribute to pharmacokinetic interactions between SOR and drugs that are substrates for CYP2C8, perhaps in those individuals in whom SNO accumulates.

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Computational Prediction of the Site(s) of Metabolism and Binding Modes of Protein Kinase Inhibitors Metabolized by CYP3A4

Cited by 15 publications

References 84 publications

Crystal Structure of CYP3A4 Complexed with Fluorol Identifies the Substrate Access Channel as a High-Affinity Ligand Binding Site

Crystal Structure of CYP3A4 Complexed with Fluorol Identifies the Substrate Access Channel as a High-Affinity Ligand Binding Site

Site of Metabolism (SOM) Predictions for Centella asiatica and Orthosiphon stamineus Marker Compounds with CYP3A4 Using a Molecular Docking Approach

Differential inhibition of human CYP2C8 and molecular docking interactions elicited by sorafenib and its major N-oxide metabolite

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