Analysis and applications of new geometrical models of active site access channels of some human cytochromes P450 for large ligands

Les cytochromes P450s (CYPs) sont des hémoprotéines intervenant dans la fonction de détoxication cellulaire. Le site actif des CYPs est enfoui dans la protéine, mais accessible aux ligands par des canaux. A l'aide d'une méthode récente basée sur la triangulation de Delaunay de la protéine, et implémentée dans le logiciel CCCPP, nous avons modélisé géométriquement ces canaux pour plusieurs isoformes humaines, dont le 3A4, présent au niveau du foie humain et responsable de la métabolisation d'un nombre important de médicaments, afin de constituer un filtre stérique destiné au criblage virtuel rapide de chimiothèques. Cette approche nous a permis d'obtenir des informations sur les mécanismes d'ouverture et de fermeture des canaux, permettant d'expliquer comment des ligands volumineux peuvent accéder au site actif. Ces résultats confirment et étendent ceux de la littérature, et peuvent contribuer à l'élaboration de médicaments nouveaux ou ayant moins d'effets secondaires.The cytochromes P450s (CYPs) are hemoproteins involved in the cellular detoxification function. The CYPs active site is buried inside the protein, but it can be accessed by the ligands through channels. With a recent method based upon the Delaunay triangulation of the protein, and implemented in the CCCPP software, we modelized geometrically these channels for several human isoforms, including the 3A4, located in the human liver and responsible of the metabolization of an important number of drugs, in order to build a sterical filter devoted to high throughput virtual screening of chemical libraries. This approach let us to get information on mechanisms of opening and closing of the channels, allowing to explain how large ligands can access to the active site. These results are in agreement and extend those found in the literature, and can contribute to the design of new drugs or of drugs having less side effects

Etude et applications de nouveaux modèles géométriques des canaux d'accès au site actif de certains cytochromes P450 humains par des ligands volumineux

The cytochromes P450s (CYPs) are hemoproteins involved in the cellular detoxification function. The CYPs active site is buried inside the protein, but it can be accessed by the ligands through channels. With a recent method based upon the Delaunay triangulation of the protein, and implemented in the CCCPP software, we modelized geometrically these channels for several human isoforms, including the 3A4, located in the human liver and responsible of the metabolization of an important number of drugs, in order to build a sterical filter devoted to high throughput virtual screening of chemical libraries. This approach let us to get information on mechanisms of opening and closing of the channels, allowing to explain how large ligands can access to the active site. These results are in agreement and extend those found in the literature, and can contribute to the design of new drugs or of drugs having less side effects.Les cytochromes P450s (CYPs) sont des hémoprotéines intervenant dans la fonction de détoxication cellulaire. Le site actif des CYPs est enfoui dans la protéine, mais accessible aux ligands par des canaux. A l'aide d'une méthode récente basée sur la triangulation de Delaunay de la protéine, et implémentée dans le logiciel CCCPP, nous avons modélisé géométriquement ces canaux pour plusieurs isoformes humaines, dont le 3A4, présent au niveau du foie humain et responsable de la métabolisation d'un nombre important de médicaments, afin de constituer un filtre stérique destiné au criblage virtuel rapide de chimiothèques. Cette approche nous a permis d'obtenir des informations sur les mécanismes d'ouverture et de fermeture des canaux, permettant d'expliquer comment des ligands volumineux peuvent accéder au site actif. Ces résultats confirment et étendent ceux de la littérature, et peuvent contribuer à l'élaboration de médicaments nouveaux ou ayant moins d'effets secondaires

Four Major Channels Detected in the Cytochrome P450 3A4: A Step toward Understanding Its Multispecificity

International audienceWe computed the network of channels of the 3A4 isoform of the cytochrome P450 (CYP) on the basis of 16 crystal structures extracted from the Protein Data Bank (PDB). The calculations were performed with version 2 of the CCCPP software that we developed for this research project. We identified the minimal cost paths (MCPs) output by CCCPP as probable ways to access to the buried active site. The algorithm of calculation of the MCPs is presented in this paper, with its original method of visualization of the channels. We found that these MCPs constitute four major channels in CYP3A4. Among the many channels proposed by Cojocaru et al. in 2007, we found that only four of them open in 3A4. We provide a refined description of these channels together with associated quantitative data

The Cytochrome P450 3A4 has three Major Conformations: New Clues to Drug Recognition by this Promiscuous Enzyme

International audienceWe computed the channels of the 3A4 isoform of the cytochrome P450 3A4 (CYP) on the basis of 24 crystal structures extracted from the Protein Data Bank (PDB). We identified three major conformations (denoted C, O1 and O2) using an enhanced version of the CCCPP software that we developed for the present work, while only two conformations (C and O 2 ) are considered in the literature. We established the flowchart of definition of these three conformations in function of the structural and physico-chemical parameters of the ligand. The channels are characterized with qualitative and quantitative parameters, and not only with their surrounding secondary structures as it is usually done in the literatur

Statistical Profiling of One Promiscuous Protein Binding Site: Illustrated by Urokinase Catalytic Domain

International audienceWhile recent literature focuses on drug promiscuity, the characterization of promiscuous binding sites (ability to bind several ligands) remains to be explored. Here, we present a proteochemometric modeling approach to analyze diverse ligands and corresponding multiple binding sub-pockets associated with one promiscuous binding site to characterize protein-ligand recognition. We analyze both geometrical and physicochemical profile correspondences. This approach was applied to examine the well-studied druggable urokinase catalytic domain inhibitor binding site, which results in a large number of complex structures bound to various ligands. This approach emphasizes the importance of jointly characterizing pocket and ligand spaces to explore the impact of ligand diversity on sub pocket properties and to establish their main profile correspondences. This work supports an interest in mining available 3D holo structures associated with a promiscuous binding site to explore its main protein-ligand recognition tendency