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Lead-Finder uses
special type of scoring function to calculate free energy of
protein-ligand binding.
This scoring function includes all energy terms (described in section Technology) scaled with a set
of coefficients, which were adjusted to fit experimentally measured binding energies.
A set of 330 protein-ligand complexes with experimentally measured binding constants
and available 3 D structures was used for the current
benchmarking study, out of which 100 complexes (the training set) were used to calibrate the scoring
function. RMSD between calculated and experimentally determined binding energies comprised
1.24 kcal/mol for the training set and
1.5 kcal/mol for the entire set
of 330 protein-ligand complexes.
About 50 % of all protein-ligand
complexes fall into ±1 kcal/mol bin
and 79 % fall into ±2 kcal/mol bin
of ΔG prediction accuracy.
These data illustrate that Lead-Finder
is the most accurate in binding energy calculations compared to other docking
programs
1,
2,
3
To make current parameterization and benchmarking studies more robust,
protein-ligand
complexes with known 3 D structure
and experimentally measured binding constants for were chosen on the basis of maximal diversity
of ligand’s physicochemical properties (molecular weight (Mw),
clog P,
number of hydrogen bond donors (dHB) and acceptors (aHB), net charge) and range
of protein – ligand
binding energies. Physicochemical properties of selected ligands
fairly cover chemical subspace satisfying
Lipinsky rule of Five
4.
However, ligands spanning beyond this subspace (57 compounds with Mw>500; 31 compounds
with clog P>5;89 compounds with (dHB+aHB)>10;
41 compounds with dHB>5) are also generously represented,
which is very important according to recent findings that physicochemical properties of drugs
are not tightly restricted by Lipinsky rule
5.
These facts support broad applicability
of Lead-Finder
for binding energy calculations.
Lead-Finder provides
unique speed of binding energy calculations compared to such methods as
free energy perturbation
or linear interaction energy, which need long molecular dynamical
simulations and generally require individual treatment of each particular task.
For the set of studied
330 protein-ligand
complexes average time for binding calculations
with Lead-Finder
comprised less than one second per compound.
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