article · Molecules
This study computationally investigates how 8-methoxypsoralen, a compound used to treat skin conditions, inhibits the enzyme cytochrome P450 1B1. Using density functional theory, molecular docking, and molecular dynamics simulations, the research examines the binding behaviour and metabolic pathways of the drug. The analysis evaluated three mechanisms of enzyme inactivation, alongside the formation of reactive metabolites through epoxide hydrolysis, non-catalysed ring opening, and covalent adduct formation. Findings reveal a slight energetic preference for the epoxidation pathway, which faces kinetic competition from demethylation. Furthermore, the active-site residue phenylalanine 268 plays a critical role by holding the compound in position and facilitating oxygen addition. The resulting covalent adducts and reactive intermediates clarify how the compound inactivates the enzyme, providing structural insights relevant to evaluating metabolic risks during therapeutic use.
Certain medications can interfere with essential drug-metabolising enzymes, potentially creating toxic by-products or causing adverse drug interactions. By mapping how 8-methoxypsoralen binds to and inactivates cytochrome P450 enzymes at the atomic scale, this computational research clarifies the chemical mechanisms behind drug toxicity. Such insights are essential for designing safer derivatives and assessing pharmacological safety profiles during pharmaceutical development.
The findings represent early-stage, computational discovery research. The molecular models and metabolic pathways identified can be used by pharmaceutical companies and preclinical drug development teams to evaluate toxicity risks of furocoumarin derivatives or design safer analogues with reduced enzyme inactivation. Because the work is purely computational, translation into commercial applications will require subsequent experimental validation through laboratory assays and safety testing.
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This study provides a comprehensive computational exploration of the inhibitory activity and metabolic pathways of 8-methoxypsoralen (8-MP), a furocoumarin derivative used for treating various skin disorders, on cytochrome P450 (P450). Employing quantum chemical DFT calculations, molecular docking, and molecular dynamics (MD) simulations analyses, the biotransformation mechanisms and the active site binding profile of 8-MP in CYP1B1 were investigated. Three plausible inactivation mechanisms were minutely scrutinized. Further analysis explored the formation of reactive metabolites in subsequent P450 metabolic processes, including covalent adduct formation through nucleophilic addition to the epoxide, 8-MP epoxide hydrolysis, and non-CYP-catalyzed epoxide ring opening. Special attention was paid to the catalytic effect of residue Phe268 on the mechanism-based inactivation (MBI) of P450 by 8-MP. Energetic profiles and facilitating conditions revealed a slight preference for the C4'=C5' epoxidation pathway, while recognizing a potential kinetic competition with the 8-OMe demethylation pathway due to comparable energy demands. The formation of covalent adducts via nucleophilic addition, particularly by phenylalanine, and the generation of potentially harmful reactive metabolites through autocatalyzed ring cleavage are likely to contribute significantly to P450 metabolism of 8-MP. Our findings highlight the key role of Phe268 in retaining 8-MP within the active site of CYP1B1, thereby facilitating initial oxygen addition transition states. This research offers crucial molecular-level insights that may guide the early stages of drug discovery and risk assessment related to the use of 8-MP.
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DOI: 10.3390/molecules29071433
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