Dataset Information

ReFlexIn: a flexible receptor protein-ligand docking scheme evaluated on HIV-1 protease.

ABSTRACT: For many targets of pharmaceutical importance conformational changes of the receptor protein are relevant during the ligand binding process. A new docking approach, ReFlexIn (Receptor Flexibility by Interpolation), that combines receptor flexibility with the computationally efficient potential grid representation of receptor molecules has been evaluated on the retroviral HIV-1 (Human Immunodeficiency Virus 1) protease system. An approximate inclusion of receptor flexibility is achieved by using interpolation between grid representations of individual receptor conformations. For the retroviral protease the method was tested on an ensemble of protease structures crystallized in the presence of different ligands and on a set of structures obtained from morphing between the unbound and a ligand-bound protease structure. Docking was performed on ligands known to bind to the protease and several non-binders. For the binders the ReFlexIn method yielded in almost all cases ligand placements in similar or closer agreement with experiment than docking to any of the ensemble members without degrading the discrimination with respect to non-binders. The improved docking performance compared to docking to rigid receptors allows for systematic virtual screening applications at very small additional computational cost.

SUBMITTER: Leis S

PROVIDER: S-EPMC3480487 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

ReFlexIn: a flexible receptor protein-ligand docking scheme evaluated on HIV-1 protease.

Leis Simon S Zacharias Martin M

PloS one 20121024 10

For many targets of pharmaceutical importance conformational changes of the receptor protein are relevant during the ligand binding process. A new docking approach, ReFlexIn (Receptor Flexibility by Interpolation), that combines receptor flexibility with the computationally efficient potential grid representation of receptor molecules has been evaluated on the retroviral HIV-1 (Human Immunodeficiency Virus 1) protease system. An approximate inclusion of receptor flexibility is achieved by using ...[more]

PMID: 23110159

Similar Datasets

Project description:BackgroundMolecular docking simulation is the Rational Drug Design (RDD) step that investigates the affinity between protein receptors and ligands. Typically, molecular docking algorithms consider receptors as rigid bodies. Receptors are, however, intrinsically flexible in the cellular environment. The use of a time series of receptor conformations is an approach to explore its flexibility in molecular docking computer simulations, but it is extensively time-consuming. Hence, selection of the most promising conformations can accelerate docking experiments and, consequently, the RDD efforts.ResultsWe previously docked four ligands (NADH, TCL, PIF and ETH) to 3,100 conformations of the InhA receptor from M. tuberculosis. Based on the receptor residues-ligand distances we preprocessed all docking results to generate appropriate input to mine data. Data preprocessing was done by calculating the shortest interatomic distances between the ligand and the receptor's residues for each docking result. They were the predictive attributes. The target attribute was the estimated free-energy of binding (FEB) value calculated by the AutodDock3.0.5 software. The mining inputs were submitted to the M5P model tree algorithm. It resulted in short and understandable trees. On the basis of the correlation values, for NADH, TCL and PIF we obtained more than 95% correlation while for ETH, only about 60%. Post processing the generated model trees for each of its linear models (LMs), we calculated the average FEB for their associated instances. From these values we considered a LM as representative if its average FEB was smaller than or equal the average FEB of the test set. The instances in the selected LMs were considered the most promising snapshots. It totalized 1,521, 1,780, 2,085 and 902 snapshots, for NADH, TCL, PIF and ETH respectively.ConclusionsBy post processing the generated model trees we were able to propose a criterion of selection of linear models which, in turn, is capable of selecting a set of promising receptor conformations. As future work we intend to go further and use these results to elaborate a strategy to preprocess the receptors 3-D spatial conformation in order to predict FEB values. Besides, we intend to select other compounds, among the million catalogued, that may be promising as new drug candidates for our particular protein receptor target.

Dataset Information

ReFlexIn: a flexible receptor protein-ligand docking scheme evaluated on HIV-1 protease.

Publications

ReFlexIn: a flexible receptor protein-ligand docking scheme evaluated on HIV-1 protease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets