Lead Finder uses a special type of scoring function to calculate free energy ofprotein-ligand binding. This scoring function includes all energy terms (described in Scoring function section) scaled with a set of coefficients that have been adjusted to fit experimentally measured binding energies.

A setof 330 protein-ligand complexes with experimentally measured binding constants and available3D structures was used for the current benchmarking study, out of which 100 complexes (the training set) were used to calibrate the scoring function. The RMSD between the calculated and experimentally determined binding energies was found to be 1.24 kcal/mol for the training set and 1.5 kcal/mol for the entire set of 330 protein-ligand complexes. About50% of all protein-ligand complexes fell into a±1 kcal/mol bin and79% fell into a±2 kcal/mol bin of_dG prediction accuracy. The data illustrate that Lead Finder has exceeded other docking software ^{1, 2, 3} in the accuracy of binding energy estimation.

To make current parameterization and benchmarking studies more meaningful, protein-ligand complexes with known3D structure and experimentally measured binding constants were chosen on the basis of maximum diversity of ligand's physicochemical properties (molecular weight (Mw), clogP, number of hydrogen bond donors (dHB) and acceptors (aHB), net charge) and range of protein - ligand binding energies. Physicochemical properties of selected ligands substantially cover chemical subspace satisfying Lipinsky's Rule of Five ⁴. However, ligands spanning beyond this subspace (57 compounds with Mw>500; 31 compounds with clogP>5; 89 compounds with (dHB+aHB)>10; 41 compounds with dHB>5) were also generously represented, which is very important according to recent findings that physicochemical properties of drugs are not tightly restrictedby Lipinsky rule ⁵. These facts support broad applicability of Lead Finder for binding energy calculations.

Lead Finder provides favorable speed of binding energy calculations compared to such methods as free energy perturbation or linear interaction energy that requires long molecular dynamical simulations and individual treatment of each particular task. For the set of studied 330 protein-ligand complexes, the average time for binding calculations withLead Finder was less than one second per compound on a standard single-processor Pentium PC.

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