A Comprehensive Analysis of Human CYP3A4 Crystal Structures as a Potential Tool for Molecular Docking-Based Site of Metabolism and Enzyme Inhibition Studies

Abstract

The notable ability of human liver cytochrome P450 3A4 (CYP3A4) to metabolize diverse xenobiotics encourages researchers to explore in-depth the mechanism of enzyme action. Numerous CYP3A4 protein crystal structures have been deposited in protein data bank (PDB) and are majorly used in molecular docking analysis. The quality of the molecular docking results depends on the three-dimensional CYP3A4 protein crystal structures from the PDB. Present review endeavors to provide a brief outline of some technical parameters of CYP3A4 PDB entries as valuable information for molecular docking research. PDB entries between 22 April 2004 and 2 June 2021 were compiled and the active sites were thoroughly observed. The present review identified 76 deposited PDB entries and described basic information that includes CYP3A4 from human genetic, Escherichia coli (E. coli) use for protein expression, crystal structure obtained from X-ray diffraction method, taxonomy ID 9606, Uniprot ID P08684, ligand–protein structure description, co-crystal ligand, protein site deposit and resolution ranges between 1.7[Formula: see text]Å and 2.95[Formula: see text]Å. The observation of protein–ligand interactions showed the various residues on the active site depending on the ligand. The residues Ala305, Ser119, Ala370, Phe304, Phe108, Phe213 and Phe215 have been found to frequently interact with ligands from CYP3A4 PDB. Literature surveys of 17 co-crystal ligands reveal multiple mechanisms that include competitive inhibition, noncompetitive inhibition, mixed-mode inhibition, mechanism-based inhibition, substrate with metabolite, inducer, or combination modes of action. This overview may help researchers choose a trustworthy CYP3A4 protein structure from the PDB database to apply the protein in molecular docking analysis for drug discovery.

Computational exploration of microsomal cytochrome P450 3A1 enzyme modulation by phytochemicals ofCichorium intybusL.: Insights into drug metabolism

“…In contrast, Ridhwan et al. (2022) reported a molecular docking study of human 3A4 with various ligands, revealing that residues Ala305, Ser119, Ala370, Phe304, Phe108, Fhe213, and Phe215 frequently interacted with CYP3A4 ligands. While Kiani et al.…”

In vitro effects and in silico analysis of newly synthetized pyrrole derivatives on the activity of different isoforms of Cytochrome P450: CYP1A2, CYP2D6 and CYP3A4

“…The docking module of Maestro -Glide was implemented for the current study considering the recent success rate when CYP enzymes were applied in the docking with the latter software (Ridhwan et al 2022). Initially, self-docking simulations were carried out to assess the reliability of the docking software to correctly generate the conformations of the co-crystallized ligands back into the active sites of CYP1A2 (PDB:2HI4), CYP2D6 (PDB:4WNU) and CY-P3A4 (PDB:2V0M).…”

“…During the latter simulations the hydrazide-hydrazone moiety was facing the hem moiety. Therefore, the implementation of IFD for virtual simulations in various CYPs isoforms is essential considering the enhanced reliability of the acquired results (Ridhwan et al 2022).…”

Design of highly active substrates using molecular docking for microbial transglutaminase detection

“…It is used as a standard computational tool in drug design for lead compound optimization. [27][28][29] In recent years, many works have begun to use molecular docking technology to identify the interactions between enzymes and ligand, based on the enzyme structure and active site can be simulated by molecular docking soware and optimal substrate-binding identied. [27][28][29][30][31] Compared with traditional experimental techniques, molecular docking is a virtual technique that uses computer simulation to analyze the interaction between receptors and ligands, which is low-cost and labor-saving.…”

“…[27][28][29] In recent years, many works have begun to use molecular docking technology to identify the interactions between enzymes and ligand, based on the enzyme structure and active site can be simulated by molecular docking soware and optimal substrate-binding identied. [27][28][29][30][31] Compared with traditional experimental techniques, molecular docking is a virtual technique that uses computer simulation to analyze the interaction between receptors and ligands, which is low-cost and labor-saving. In particular, the method of combining computational analysis and experimental assays is a reasonable strategy to achieve effectively evaluation of many protein reactions.…”