Ligand efficiency (LE) is an important parameter widely used in drug development. It is generally calculated by molecular size scaling affinity and has a non-trivial dependence on the concentration unit used to express affinity. During fragment-to-lead optimization, Creative Biolabs defines efficiency based on the sensitivity of affinity to molecular size, eliminating the dependence of ligand efficiency on concentration units. In general, it is important to examine the relationship between affinity and molecular size and proposed a method to assess LE to standardize affinity relative to molecular size. In the context of specific goals, optimizing ligand efficiency based on molecular size and lipophilicity has the potential to improve molecular swelling that is prevalent in medicinal chemistry practice and increase the developability of drug candidates.
Binding Thermodynamics and LE
Hit-to-lead usually starts when a fragment hits a target with micromolar (μM) affinity or even low millimolar (mM) affinity. Candidate molecules with ideal physicochemical properties can be identified for subsequent optimization. Among them, the combined negative free energy will increase with the improvement of efficiency, and the negative free energy is composed of two thermodynamic quantities: binding enthalpy and binding entropy.
Considering the well-known entropy-enthalpy compensation phenomenon, it is very difficult to predict how the structural modification will affect the combined enthalpy or entropy, but there are some general trends for reference. Optimization of specific polar interactions between target binding sites and ligands is often associated with more promising physicochemical properties (lower lipophilicity) and improved binding enthalpy. In contrast to the binding free energy, when the number of heavy atoms is 25 or more, the binding enthalpy decreases with increasing molecular size, and LE decreases with an increasing number of heavy atoms.
Fig.1 Enthalpy and entropy ligand efficiencies versus properties. (McCoy, 2014)
LE Assessment Services
LE plays an important role in fragment-based clue discovery (FBLD) and is sometimes considered an important basis for screening fragments. LE measurement provides an estimate of the physical properties of the affinity of a drug target, which can be used as a basis to optimize the physical properties of a drug and increase affinity.
LE, as a quantifiable value, represents the binding energy of a compound normalized by its size and is usually expressed in terms of the number of heavy (non-hydrogen) atoms. A common method for calculating LE is to divide the Gibbs binding free energy (ΔG) by the number of heavy atoms (N), that is: LE = (ΔG) / N. Using the thermodynamic equation of Gibbs free energy ΔG = − RTlnKi and replacing Ki with IC50 (less strict approximation), the ligand efficiency can be calculated as follows:
LE = 1.4 (pIC50) / N
Creative Biolabs' LE Assessment service can help clients improve the following areas in the drug development process:
If you are interested in our drug evaluation services, you can contact us for more details.
Reference
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