Ligand critical interaction with receptor

Atoms in molecules are first classified into different pharmacophoric types by the GRID force field parametrization. Features considered are hydrophobicity, hydrogen-bond donor and acceptor capabilities, and charge. Then, all accessible geometries for all the combinations of three or four features are calculated and encoded in the final vector. Fingerprints can be calculated both for ligands and proteins. In small ligands, pharmacophores are defined by triplets or quartets of atoms, vhich have critical interactions with a receptor. 

Before the elucidation of the CAR X-ray crystal structure, modeling studies mainly focused on the constitutive activity of the receptor. For example, homology modeling along with molecular dynamics simulations was combined to identify critical amino acid residues responsible for the constitutive activation [43]. Especially, the role of Tyr326 as a molecular mimicry of a bound ligand in the interaction with the AF-2 helix was underscored. Mutational analyses and the later elucidation of the human CAR X-ray crystal structure confirmed an important role of this amino acid for the receptor s constitutive activity [41,44]. 

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