Abstract
Cytochrome P450 2C9 (CYP2C9) metabolizes about 15% of clinically administrated drugs. The allelic variant CYP2C9*30 (A477T) is associated to diminished response to the antihypertensive effects of the prodrug losartan and affected metabolism of other drugs. Here, we investigated molecular mechanisms involved in the functional consequences of this amino-acid substitution. Molecular dynamics (MD) simulations performed for the active species of the enzyme (heme in the Compound I state), in the apo or substrate-bound state, and binding energy analyses gave insights into altered protein structure and dynamics involved in the defective drug metabolism of human CYP2C9.30. Our data revealed an increased rigidity of the key Substrate Recognition Sites SRS1 and SRS5 and shifting of the β turn 4 of SRS6 toward the helix F in CYP2C9.30. Channel and binding substrate dynamics analyses showed altered substrate channel access and active site accommodation. These conformational and dynamic changes are believed to be involved in the governing mechanism of the reduced catalytic activity. An ensemble of representative conformations of the WT and A477T mutant properly accommodating drug substrates were identified, those structures can be used for prediction of new CYP2C9 and CYP2C9.30 substrates and drug-drug interactions.
Highlights
Cytochrome P450 2C9 (CYP2C9) is the most expressed member of the human CYP2C family and metabolizes more than 15% of clinically administrated drugs including hypoglycemic agents, anticonvulsants, anticoagulants, nonsteroidal anti-inflammatory drugs (NSAIDs), antihypertensives, diuretic drugs [1,2,3] and several endogenous compounds [4]
To elucidate the molecular mechanisms involved in the defected metabolism of CYP2C9.30 we performed molecular dynamics simulations of the active species of the WT of CYP2C9 and the mutant A477T, both containing the heme in the Compound I state (Cpd I) [24]
A larger number of acceptable poses for the catalytic reaction were obtained for the WT as compared to the mutant for the most representative centroids. These results indicated that some conformations of the A477T mutant were still able to accommodate the substrates, mutant conformations that properly bound the substrates were visited for a shorter period of time of the Molecular dynamics (MD) simulations compared to the WT
Summary
Cytochrome P450 2C9 (CYP2C9) is the most expressed member of the human CYP2C family and metabolizes more than 15% of clinically administrated drugs including hypoglycemic agents, anticonvulsants, anticoagulants, nonsteroidal anti-inflammatory drugs (NSAIDs), antihypertensives, diuretic drugs [1,2,3] and several endogenous compounds [4]. The genetic variations resulting mainly from single nucleotide polymorphisms (SNPs) explain a large part of the inter-individual variability in the activity of CYP enzymes [5]. More than 50 variants of CYP2C9 have shown decreased enzymatic activity [3, 6,7,8]. Polymorphisms of CYP2C9 can affect the clinical response of drugs metabolized by CYP2C9, especially those with a narrow therapeutic index and can induce adverse drug reactions (ADR).
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