Estimation of Free Energy of Binding in Protein-Ligand Complexes

By: Biomoltech  09-12-2011
Keywords: Molecular Modeling, Docking Software,

Binding Energy Estimation

Lead Finder is capable of predicting free energy of protein-ligand binding with high accuracy. This functionality is novel to docking software since binding energy calculation is usually done in separate software packages that are based on various theoretical approaches including free energy perturbation, linear interaction energy, etc. Such packages require high level of expertise and involvement in specific fields of computational chemistry and are often expensive and time-consuming to implement.

Lead Finder performs high-accuracy calculation of the free energy of binding at the same time when a ligand docking computation is done. A separate scoring function, called dG-score function, is used to calculate binding energy of protein-ligand interaction. The accuracy of binding energy prediction with Lead Finder has been validated on a set of 330 experimentally characterized protein-ligand complexes with a broad distribution of ligand binding affinities and other physicochemical properties (see the

section for more details). On this test set, Lead Finder has achieved an RMSD of 1.5 kcal/mol (deviation from the experimentally obtained values).

Binding energy calculations can be performed either concurrently with ligand docking or separately for a predetermined protein-ligand structure, obtained from experimental data or other molecular modeling studies. The ability of Lead Finder to accurately predict free energy of ligand binding can be extremely valuable in drug discovery studies, modeling ADMET properties in silico, studies of enzyme specificity and rational enzyme design.

Keywords: Docking Software, Molecular Modeling,

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Lead Finder - a software solution for virtual screening and molecular docking

Accuracy of protein-ligand docking has been validated on a set of 407 protein-ligand complexes, which appears to be the most extensive benchmarking study of such kind at present. However, virtual screening, ligand docking and estimation of binding energy of protein-ligand interaction are clearly the three primary application areas for Lead Finder.


Pre-docking Preparation of Protein Structures

Lead Finder uses an original theoretical approach to assign optimal ionization states of protein residues at arbitrary pH conditions, which is based on the recently introduced screened coulomb potential model. SCP theory treats microenvironment-dependent energy of electrostatic interactions as a function of local hydrophilicity and degree of solvent exposure.


Prediction of 3D structure of protein-ligand complexes

While many configuration options are available to end users to fine-tune docking calculations, two calculation regimes, docking and screening, have been created to provide the optimum balance between the speed of calculations and the accuracy of predictions.


Virtual Screening of Libraries of Chemical Compounds

To accelerate processing of large libraries in virtual screening experiments, Lead Finder employs a special modification of the docking algorithm called screening mode. During virtual screening each ligand from a library is docked to a target protein, and ligands are rank-ordered according to their binding potencies.