Ligand receptor-bound conformation

Knowledge of the receptor-bound conformation of a ligand is of great help in drug design. Constraints can then be introduced to encourage... 

Substructure searches in topological (2D) databases of compounds of diverse sources (e.g., commercially available compounds, company database) are extensively used by medicinal chemists to preselect substances for screening. Since the pharmacological action is mediated through the 3D shape of the ligand molecule in the receptor-bound conformation, efforts have been made in recent years to construct low-energy 3D structures from 2D databases. A pharmacophore hypothesis can be derived from a series of known inhibitors and their consensus 3D features. 

A search method was considered to be able to reproduce the receptor-bound conformation for a certain ligand when at least one structure in the generated ensemble... 

Embodied in Eq. [7] are two key assumptions. First, the interaction energy between a ligand and receptor can be partitioned into the individual interaction energies between an atom or a group of atoms of the molecule with the complementary receptor atoms. Second, as in Eq. [5] for explicit receptor binding site models, the lower the internal energy of the molecule required to attain the receptor-bound conformation, the higher will be the potency. 

An upper limit for dissociation constants in the rtiQUmolar range is mainly given by the solubility of receptor or ligand and the occurrence of nonspecific binding processes which make the determination of a single bound conformation obsolete. 

These novel methodologies have also been applied to access to conformational information in the bound state. For a ligand-receptor complex in solution, averaged RDC are measured for the ligand atom pairs, which depend on the ligand molar ratio of the sugar when free and when... 

Measurements of the trCCR-rate have also been applied to small pep-tidic ligands. In a proof-of-concept study we have studied the STAT-6 bound conformation of an IL-4 receptor-derived peptide [9]. For this study a chemically synthesized N/ C-labelled tetrapeptide was used in conjunction with NHCH dipole-dipole CCR and /nhc dipole-CSA CCR experiments. 

The investigation of protein (and receptor) structure, ligand-receptor binding, and differences between the conformation of an unbound, but solvated, and receptor-bound ligand by NMR needs an amalgamation of the skills of molecular biologists, spectroscopists and computational chemists. 

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