Discovery of Naturally Occurring Flavonoids as Human Cytochrome P450 (CYP3A4) Inhibitors with the Aid of Computational Chemistry

Abstract

Purpose: The human cytochrome P450 3A4 (CYP3A4) is the biggest individual from the CYP3A subfamily and records for 30-60% of the total for CYP450 adult liver. Hereditary varieties in CYP3A4 are a noteworthy hotspot for inter-patient changeability in plasma concentration, adverse effects and pharmacological response to medications. This research was done to discover naturally occurring novel CYP3A4 inhibitors from flavonoids. Methods: The molecular docking method was used to optimize the inhibiting activity of flavonoids against CYP3A4. PyRx Virtual Screening Tool 0.8 and BIOVIA Discovery Studio 2019 was used for simulation. Results: Flavonoids like Pongamoside A, Pongamoside B, and Pongamoside D have more binding affinity (kcal/mol) i.e. -11.6, -10.9, -10.8 respectively than Doxorubicin which have -10.7 against CYP3A4. Although, Daidzein, Genistein, and Luteolin form more hydrogen bonds than doxorubicin. Conclusion: The rational synthesis of natural analogues in reference to synthetic drugs, could generate drugs with improved therapeutic effect for chemoprevention. CYP3A4 plays a major role in the metabolism of various drugs; by the help of flavonoids, we can control the selective drug metabolism by inhibiting CYP3A4. Despite this, these molecules are not marketed for cancer treatment because of high polarity. If we could overcome this problem, these molecules can acts as effective anticancer agents in the future. Still, if we want to use these compounds clinically, there is a need to generate more scientific evidence and quality data by using in vivo and in vitro models.

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