Principles of ligand design

Ligand design

Ligand: a molecule of any size that binds or interacts with another molecule through noncovalent forces (usually not involving chemical bond formation).

Target or receptor: usually the larger species.

Interactions:

• chemical/physical forces between ligand and receptor,
• and between each of these molecules and the solvent or environment.

Study of the interactions:

• fundamentally using quantum mechanics (limited by computational resources),
• other empirical computational approaches,
• comparison with experiments.

Properties connected to thermodynamics: free energy of binding, solubility in aqueous and nonaqueous enviroments, and so forth.

Kinetics: less often considered, but important in enzyme catalisis, signaling cascades, and molecular rearrangements.

Free energy of binding (difference in the free energy of the complex and the free energy of its components, the receptor and the ligand):

$\Delta G_{bi n d} = \Delta G_{compl e x} - (\Delta G_{liga nd} + \Delta G_{recept o r})$

$\Delta G_{bi n d}$ is a function of temperature, pressure, ionic strength, pH, solvent, and concentratrion of all the chemical species present.

Experimental measurent: $\Delta G_{bi n d} = -RT \ln K_{e q} = RT \ln K_{d}$

Personal working notes extracted from "Principles and Methods of Docking and Ligand Design" in Structural Bioinformatics