3 research outputs found
Effect of the explicit flexibility of the InhA enzyme from Mycobacterium tuberculosis in molecular docking simulations
Background: Protein/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).
Results: The 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.
Conclusions: Protein/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 dynamicalstructure-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