Docking is a computational technique that samples conformations of small molecules in protein binding sites; scoring functions are used to assess which of these conformations best complements the protein binding site. An evaluation of 10 docking programs and 37 scoring functions was conducted against eight proteins of seven protein types for three tasks: binding mode prediction, virtual screening for lead identification, and rank-ordering by affinity for lead optimization. All of the docking programs were able to generate ligand conformations similar to crystallographically determined protein/ligand complex structures for at least one of the targets. However, scoring functions were less successful at distinguishing the crystallographic conformation from the set of docked poses. Docking programs identified active compounds from a pharmaceutically relevant pool of decoy compounds; however, no single program performed well for all of the targets. For prediction of compound affinity, none of the docking programs or scoring functions made a useful prediction of ligand binding affinity.

The B3-LYP/6-311+G(3df,2p)//B3-LYP/6-31G(d) procedure has been used to study the zeolite-catalyzed hydrogenation of prototypical doubly bonded systems. Both Brønsted acid and alkali metal sites in model zeolites have been examined. For the hydrogenation of ethene, the barrier is predicted to be lowered by about 50% at the Brønsted acid sites and by about 40% at the alkali metal sites. The barriers for the hydrogenation of formimine and formaldehyde are predicted to be lowered even more substantially, with remarkably low overall barriers of 30 and 60 kJ mol-1, respectively, at the Brønsted acid sites of the zeolites. The alkali metal sites of the zeolites are found to be not quite as effective as the Brønsted acid sites in lowering the hydrogenation barriers in these two cases, as for ethene. Comparisons are made with relevant experimental data.

Background and purpose: Several P2X 7 receptor antagonists are allosteric inhibitors and exhibit species difference in potency. Furthermore, N 2 -(3,4-difluorophenyl)-N 1 -(2-methyl-5-(1-piperazinylmethyl)phenyl)glycinamide dihydrochloride (GW791343) exhibits negative allosteric effects at the human P2X 7 receptor but is a positive allosteric modulator of the rat P2X 7 receptor. In this study we have identified several regions of the P2X 7 receptor that contribute to the species differences in antagonist effects. Experimental approach: Chimeric human-rat P2X 7 receptors were constructed with regions of the rat receptor being inserted into the human receptor. Antagonist effects at these receptors were measured in ethidium accumulation and radioligand binding studies. Key results: Exchanging regions of the P2X 7 receptor close to transmembrane domain 1 modified the effects of KN62, 4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) and GW791343. Further studies, in which single amino acids were exchanged, identified amino acid 95 as being primarily responsible for the differential allosteric effects of GW791343 and, to varying degrees, the species differences in potency of SB203580 and KN62. The species selectivity of pyridoxalphosphate-6-azophenyl-2 0 ,4 0 -disulphonic acid was affected by multiple regions of the receptor, with potency being particularly affected by the amino acid 126 but not by amino acid 95. A further region of the rat receptor (amino acids 154-183) was identified that, when inserted into the corresponding position in the human receptor, increased ATP potency 10-fold. Conclusions: This study has identified several key residues responsible for the species differences in antagonist effects at the P2X 7 receptor and also identified a further region of the P2X 7 receptor that can significantly affect agonist potency at the P2X 7 receptor.