Virtual Screening of Libraries of Chemical Compounds

By: Biomoltech  09-12-2011

Virtual Screening

Lead Finder performs virtual screening of libraries of chemical compounds to find most potent binders for a given target protein. During virtual screening each ligand from a library is docked to a target protein, and ligands are rank-ordered according to their binding potencies.

To distinguish active compounds from the inactive ones more effectively, a special type of scoring function (called VS-score) has been implemented in Lead Finder. This scoring function employs the same energy contributions as other scoring functions of the Lead Finder (see

section for details), however the energy scaling coefficients have been specifically adjusted to attain better enrichment factors in virtual screening experiments.

To accelerate processing of large libraries in virtual screening experiments, Lead Finder employs a special modification of the docking algorithm called screening mode. Structure processing is on average 2-4 times faster in the screening mode than in the default docking mode. The fast screening mode does not lead to a significant loss of accuracy of free energy of binding prediction and docking success rate (see the

section for details).

Efficiency of Lead Finder in virtual screening has been benchmarked on a set of 34 therapeutically relevant protein targets for which crystallographic structures and sets of potent inhibitors are available from the public domain. As can be seen from the

section Lead Finder has been able to achieve impressive enrichments for almost all protein targets in the test set.

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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.


Estimation of Free Energy of Binding in Protein-Ligand Complexes

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.