Structure-Based Drug Design for Cytochrome P450 Family 1 Inhibitors

Abstract

Cytochromes P450 are a class of metalloproteins which are responsible for electron transfer in a wide spectrum of reactions including metabolic biotransformation of endogenous and exogenous substrates. The superfamily of cytochromes P450 consists of families and subfamilies which are characterized by a specific structure and substrate specificity. Cytochromes P450 family 1 (CYP1s) play a distinctive role in the metabolism of drugs and chemical procarcinogens. In recent decades, these hemoproteins have been intensively studied with the use of computational methods which have been recently developed remarkably to be used in the process of drug design by the virtual screening of compounds in order to find agents with desired properties. Moreover, the molecular modeling of proteins and ligand docking to their active sites provide an insight into the mechanism of enzyme action and enable us to predict the sites of drug metabolism. The review presents the current status of knowledge about the use of the computational approach in studies of ligand-enzyme interactions for CYP1s. Research on the metabolism of substrates and inhibitors of CYP1s and on the selectivity of their action is particularly valuable from the viewpoint of cancer chemoprevention, chemotherapy, and drug-drug interactions.

Inhibition of human CYP1 enzymes by a classical inhibitor α‐naphthoflavone and a novel inhibitor N‐(3, 5‐dichlorophenyl)cyclopropanecarboxamide: An in vitro and in silico study

“…Although the identity between CYP1As and CYP1B1 is relatively low (<40%), there is a substantial substrate overlap. All three CYP1 family enzymes possess relatively small binding cavities, to which planar substrates such as melatonin, polycyclic aromatic hydrocarbons, and xanthines fit well (Dutkiewicz & Mikstacka, 2018; Raunio, Kuusisto, Juvonen, & Pentikainen, 2015; Sridhar, Goyal, Liu, & Foroozesh, 2017; Zhou, Wang, Yang, & Liu, 2010).…”

Analysis of the Molecular Interactions between Cytochromes P450 3A4 and 1A2 and Aflatoxins: A Docking Study

“…The observed differences in the interactions between CYP450 and AF, using several approaches of molecular modeling, provide a better understanding of the AF-CYP450 complex. Techniques like molecular docking and quantum chemical methods [36] and multivalent/multitargeted systems [37] This level of interaction between amino acids and ligands could be related to the charge transfer values, which means that the higher the ∆N values, the higher the interaction between compounds [34,35]. As was expected, the HEM group was responsible for the main interaction in the active site, with ∆N values higher than 0.6.…”

“…The observed differences in the interactions between CYP450 and AF, using several approaches of molecular modeling, provide a better understanding of the AF-CYP450 complex. Techniques like molecular docking and quantum chemical methods [36] and multivalent/multitargeted systems [37] are efficient approaches to determine the drug-macromolecule interactions and can lead to the design of specific drugs for the prevention or treatment for the toxicity of these aflatoxins.…”

Application of Various Molecular Modelling Methods in the Study of Estrogens and Xenoestrogens

“…MD serves also as a tool to explain the results of molecular docking. For example, it has been stated that the interactions between human α-fetoprotein and agonists (estradiol, estrone, diethylsilbestrol) were caused by van der Waals forces, whereas binding of antagonists (tamoxifen and its analogues) was equally based on hydrophobic and electrostatic interactions [ 129 ]. Moreover, information from MD simulations can be used to construct a pharmacophore in order to screen protein databases for a desired type of ligand.…”