Ligand efficiency is a measurement of the
binding energy
In physics and chemistry, binding energy is the smallest amount of energy required to remove a particle from a system of particles or to disassemble a system of particles into individual parts. In the former meaning the term is predominantly use ...
per atom of a
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
to its binding partner, such as a receptor or enzyme.
Ligand efficiency is used in
drug discovery research programs to assist in narrowing focus to
lead compound
A lead compound (, i.e. a "leading" compound, not to be confused with various compounds of the metallic element lead) in drug discovery is a chemical compound that has pharmacology, pharmacological or biological activity likely to be therapeutical ...
s with optimal combinations of physicochemical properties and pharmacological properties.
Mathematically, ligand efficiency (LE) can be defined as the ratio of
Gibbs free energy
In thermodynamics, the Gibbs free energy (or Gibbs energy; symbol G) is a thermodynamic potential that can be used to calculate the maximum amount of work that may be performed by a thermodynamically closed system at constant temperature and ...
(ΔG) to the number of non-hydrogen atoms of the compound:
:LE = (Δ''G'')/''N''
where Δ''G'' = −''RT''ln''K
i'' and ''N'' is the number of non-hydrogen atoms.
It can be transformed to the equation:
:LE = 1.4(−log IC
50)/''N''
Other metrics
Some suggest
[ that better metrics for ligand efficiency are
percentage/potency efficiency index (PEI), binding efficiency index (BEI) and surface-binding efficiency index (SEI) because they are easier to calculate and take into account the differences between elements in different rows of the periodic table. It is important to note that PEI is a relative measure for comparing compounds tested in the same conditions (e.g. a single-point assay) and are not comparable at different inhibitor concentrations. Also for BEI and SEI, similar measurements must be used (e.g. always using pKi).
:PEI = (% inhibition at a given compound concentration as fraction: 0 – 1.0) / (molecular weight, kDa)
:BEI = (pKi, pKd, or pIC50) / (molecular weight, kDa)
:SEI = (pKi, pKd, or pIC50) / (PSA/100 Å)
where pKi, pKd and pIC50 is defined as −log(Ki), −log(Kd), or −log(IC
50), respectively. Ki and IC50 in mol/L.
The authors suggest plotting compounds SEI and BEI on a plane and optimizing compounds towards the diagonal and so optimizing both SEI and BEI which incorporate potency, molecular weight and PSA.][
There are other metrics which can be useful during hit to lead optimization: group efficiency (GE), lipophilic efficiency/lipophilic ligand efficiency (LipE/LLE), ligand lipophilicity index (LLEAT) ligand efficiency dependent lipophilicity (LELP), fit quality scaled ligand efficiency (LEscale), size independent ligand efficiency (SILE).]
See also
* Drug design
Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that acti ...
* Drug discovery hit to lead
Hit to lead (H2L) also known as lead generation is a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds. These lead compo ...
References
Drug discovery
Medicinal chemistry
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