Effect of the explicit flexibility of the InhA enzyme from Mycobacterium tuberculosis in molecular docking simulations

BMC Genomics

Proceedings

Karina S Machado¹  Marcelo Cohen¹  Osmar Norberto de Souza²  Elisangela ML Cohen² 

[1] Laboratório de Bioinformática, Modelagem e Simulação de Biossistemas - LABIO, Programa de Pós-Graduação em Ciência da Computação - PPGCC - Faculdade de Informática - PUCRS, Av. Ipiranga, 6681 Prédio 32 - Sala 608, CEP: 90619-900, Porto Alegre, RS, Brasil;Laboratório de Bioinformática, Modelagem e Simulação de Biossistemas - LABIO, Programa de Pós-Graduação em Ciência da Computação - PPGCC - Faculdade de Informática - PUCRS, Av. Ipiranga, 6681 Prédio 32 - Sala 608, CEP: 90619-900, Porto Alegre, RS, Brasil;Programa de Pós-Graduação em Biologia Celular e Molecular - PPGBCM - Faculdade de Biociências - PUCRS, Av. Ipiranga, 6681 Prédio 12, CEP: 90619-900, Porto Alegre, RS, Brasil;

关键词: Molecular Dynamic Simulation;    Virtual Screening;    Triclosan;    Docking Simulation;    Ethionamide;   

DOI  :  10.1186/1471-2164-12-S4-S7

来源: Springer

【 摘 要 】

BackgroundProtein/receptor explicit flexibility has recently become an important feature of molecular docking simulations. Taking the flexibility into account brings the docking simulation closer to the receptors’ real behaviour in its natural environment. Several approaches have been developed to address this problem. Among them, modelling the full flexibility as an ensemble of snapshots derived from a molecular dynamics simulation (MD) of the receptor has proved very promising. Despite its potential, however, only a few studies have employed this method to probe its effect in molecular docking simulations. We hereby use ensembles of snapshots obtained from three different MD simulations of the InhA enzyme from M. tuberculosis (Mtb), the wild-type (InhA_wt), InhA_I16T, and InhA_I21V mutants to model their explicit flexibility, and to systematically explore their effect in docking simulations with three different InhA inhibitors, namely, ethionamide (ETH), triclosan (TCL), and pentacyano(isoniazid)ferrate(II) (PIF).ResultsThe use of fully-flexible receptor (FFR) models of InhA_wt, InhA_I16T, and InhA_I21V mutants in docking simulation with the inhibitors ETH, TCL, and PIF revealed significant differences in the way they interact as compared to the rigid, InhA crystal structure (PDB ID: 1ENY). In the latter, only up to five receptor residues interact with the three different ligands. Conversely, in the FFR models this number grows up to an astonishing 80 different residues. The comparison between the rigid crystal structure and the FFR models showed that the inclusion of explicit flexibility, despite the limitations of the FFR models employed in this study, accounts in a substantial manner to the induced fit expected when a protein/receptor and ligand approach each other to interact in the most favourable manner.ConclusionsProtein/receptor explicit flexibility, or FFR models, represented as an ensemble of MD simulation snapshots, can lead to a more realistic representation of the induced fit effect expected in the encounter and proper docking of receptors to ligands. The FFR models of InhA explicitly characterizes the overall movements of the amino acid residues in helices, strands, loops, and turns, allowing the ligand to properly accommodate itself in the receptor’s binding site. Utilization of the intrinsic flexibility of Mtb’s InhA enzyme and its mutants in virtual screening via molecular docking simulation may provide a novel platform to guide the rational or dynamical-structure-based drug design of novel inhibitors for Mtb’s InhA. We have produced a short video sequence of each ligand (ETH, TCL and PIF) docked to the FFR models of InhA_wt. These videos are available at http://www.inf.pucrs.br/~osmarns/LABIO/Videos_Cohen_et_al_19_07_2011.htm.

【 授权许可】

Unknown   
© Cohen et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.