Ligand 3D structures

When R is the reactivity of the atom i in the appropriate reaction mechanism, it represents the activation energy required to produce the reactive intermediate. It depends on the ligand 3D structure and on the mechanism of reaction. Therefore, R, is a score proportional to the reactivity of the ligand atom i in a specific reaction mechanism. 

The accessibility component, represents the recognition between the specific CYP-protein and the ligand when the ligand is positioned in the CYP-protein and exposes the atom i to the heme. It depends on the ligand 3D structure, conformation, chirality, and on the 3D structure and sidechain flexibility of the CYP-enzyme. Thus the score is proportional to the exposure of the ligand atom i to the heme group of a specific CYP-enzyme. 

The PDB contains 20 254 experimentally determined 3D structures (November, 2002) of macromolecules (nucleic adds, proteins, and viruses). In addition, it contains data on complexes of proteins with small-molecule ligands. Besides information on the structure, e.g., sequence details (primary and secondary structure information, etc.), atomic coordinates, crystallization conditions, structure factors. 

The SBDD approach affected computational chemists positively. The increased number of 3D structures of therapeutically relevant targets opened new opportunities for molecular modeling of the receptor sites. Computational chemists assisted the medicinal chemists in interpreting the fruits of crystallography for design of new ligands. 

The 3D structure of the 2,3-diphosphoglycerate (DPG) complex of hemoglobin (Hb) served to derive simple aromatic dialdehydes that mimic the function of DPG as an allosteric modulator of the oxygen affinity of Hb. Some of the resulting compounds were as active and even more active than DPG, the natural ligand [1-3]. 

NMR 3D structure of the undecapeptide U-II generated a ligand pharmacophore hypothesis that served as query for the virtual screening of the Aventis in-house compound repository. Active leads from six different chemical classes could be identihed by the 3D search, for example, compound 17 (ECso = 400nM Fig. 16.2) [91]. 

CombiSMoG potential function, which was derived from 1000 protein-ligand complex 3D structures. After inspection of 100,000 candidates, the hve best hits were ranked by a force field calculation. The (i )-isomer of the indole compound 59 (K = 30 pM Fig. 16.8) is the highest-scoring compound and has the highest affinity of all synthesized molecules, whereas the (S) -isomer has only K = 230 pM [131,132]. 

Bcl-2 is one of the many factors that control apoptosis, and overexpression of Bcl-2 has been observed in many different cancers. A homology model of Bcl-2 was derived from the NMR 3D structure of the Bcl-XL complex with a Bak BH3 peptide. This model served to search the NCI 3D database of 206,876 organic compounds for potential Bcl-2 inhibitors, which bind to the Bak BH3 binding site of Bcl-2. Full conformational flexibility of the ligands was taken into account in the program DOCK. Thirty-five potential inhibitors were tested, and seven of them had IC50 values from 1.6 to W.OpM. One of... 

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