Identifying the Binding Residues on CYP3A4 to Naringin Using Protein Modeling and Docking
Abstract
Cytochrome p450 3A4 (CYP3A4) is one of the most abundant cytochrome enzymes and is involved in the detoxification of many medically relevant drugs. Inhibition of CYP3A4 can increase the bioavailability and duration of the availability of medications in the bloodstream and is therefore of great medical relevance. CYP3A4 has been noted to be inhibited by naringin, a flavanone found in grapefruits and other citrus fruits. As no structure exists of naringin bound to CYP3A4, the binding residues to naringin were investigated using 3-D protein modeling and in-silico molecular docking simulations. The CYP3A4 protein structure was obtained from the RCSB Protein Data Bank (8DYC) and modified to remove all substrates except the prosthetic heme group. The PyRx program was used to conduct molecular docking simulations and the resulting docked position of naringin was compared to the positions of other known inhibitors and substrates. The specific residue interactions were identified using the USCF Chimera Contacts/Clashes feature. A 3-D model was developed to show the docked position of naringin in CYP3A4. The residues Arg 372 and Thr 224, which form the opening of the cleft, in addition to the active site residues Glu 374, Arg 106, Arg 105, Ala 370, Phe 215, Arg 212, Phe 304, and Ser 119, and the additional residues Ile 223 and Leu 482 were all found to be involved in the binding to naringin. Overall, our results indicate that naringin may inhibit CYP3A4 by blocking the cleft opening and the active site.
Faculty Sponsors
Dr. Emily Schmitt Lavin, Dr. Arthur Sikora
Project Type
Event
Location
Alvin Sherman Library
Start Date
4-3-2024 12:30 PM
End Date
4-4-2024 1:30 PM
Identifying the Binding Residues on CYP3A4 to Naringin Using Protein Modeling and Docking
Alvin Sherman Library
Cytochrome p450 3A4 (CYP3A4) is one of the most abundant cytochrome enzymes and is involved in the detoxification of many medically relevant drugs. Inhibition of CYP3A4 can increase the bioavailability and duration of the availability of medications in the bloodstream and is therefore of great medical relevance. CYP3A4 has been noted to be inhibited by naringin, a flavanone found in grapefruits and other citrus fruits. As no structure exists of naringin bound to CYP3A4, the binding residues to naringin were investigated using 3-D protein modeling and in-silico molecular docking simulations. The CYP3A4 protein structure was obtained from the RCSB Protein Data Bank (8DYC) and modified to remove all substrates except the prosthetic heme group. The PyRx program was used to conduct molecular docking simulations and the resulting docked position of naringin was compared to the positions of other known inhibitors and substrates. The specific residue interactions were identified using the USCF Chimera Contacts/Clashes feature. A 3-D model was developed to show the docked position of naringin in CYP3A4. The residues Arg 372 and Thr 224, which form the opening of the cleft, in addition to the active site residues Glu 374, Arg 106, Arg 105, Ala 370, Phe 215, Arg 212, Phe 304, and Ser 119, and the additional residues Ile 223 and Leu 482 were all found to be involved in the binding to naringin. Overall, our results indicate that naringin may inhibit CYP3A4 by blocking the cleft opening and the active site.
