Smart screening: approaches to efficient HTS.

Faced with the prospect of a rising number of potential drug targets and given almost unlimited access to internal and external chemistry resources, the 'brute-force' approach to high-throughput screening (HTS) is becoming increasingly unattractive. Pharmaceutical companies realize that they have both to increase the scope of screening experiments and improve on the efficiency of the screening process per se. In acknowledging this development, hybrid screening strategies have been suggested that unite in silico and in vitro screening in one integrated process. The partnering of both screening approaches in one process is believed to exploit the potential of HTS in much smarter and more cost-efficient ways. This review will describe some recent applications of this new screening paradigm and discuss the impact of integrating these novel strategies in the drug discovery process.

Prediction of ligand-receptor binding thermodynamics by free energy force field three-dimensional quantitative structure-activity relationship analysis: applications to a set of glucose analogue inhibitors of glycogen phosphorylase.

Glucose analogue inhibitors of glycogen phosphorylase, GP, may be of clinical interest in the regulation of glycogen metabolism in diabetes. The receptor geometry of glycogen phosphorylase b, GPb, is available for structure-based design and also for the evaluation of the thermodynamics of ligand-receptor binding. Free energy force field (FEFF) 3D-QSAR analysis was used to construct ligand-receptor binding models. FEFF terms involved in binding are represented by a modified first-generation AMBER force field combined with a hydration shell solvation model. The FEFF terms are then treated as independent variables in the development of 3D-QSAR models by correlating these energy terms with experimental binding energies for a training set of inhibitors. The genetic function approximation, employing both multiple linear regression and partial least squares regression data fitting, was used to develop the FEFF 3D-QSAR models for the binding process and to scale the free energy force field for this particular ligand-receptor system. The significant FEFF energy terms in the resulting 3D-QSAR models include the intramolecular vacuum energy of the unbound ligand, the intermolecular ligand-receptor van der Waals interaction energy, and the van der Waals energy of the bound ligand. Other terms, such as the change in the stretching energy of the receptor on binding, change in the solvation energy of the system on binding, and the change in the solvation energy of the ligand on binding are also found in the set of significant FEFF 3D-QSAR models. Overall, the binding of this class of ligands to GPb is largely characterized by how well the ligand can sterically fit into the active site of the enzyme. The FEFF 3D-QSAR models can be used to estimate the binding free energy of any new analogue in substituted glucose series prior to synthesis and testing.

Anticonvulsant activity of novel derivatives of 2- and 3-piperidinecarboxylic acid in mice and rats.

The relative ability of derivatives of 2-piperidinecarboxylic acid (2-PC; pipecolic acid) and 3-piperidinecarboxylic acid (3-PC; nipecotic acid) to block maximal electroshock (MES)-induced seizures, elevate the threshold for electroshock-induced seizures and be neurotoxic in mice was investigated. Protective index (PI) values, based on the MES test and rotorod performance, ranged from 1.3 to 4.5 for 2-PC benzylamides and from < 1 to > 7.2 for 3-PC derivatives. PI values based on elevation of threshold for electroshock-induced seizures and rotorod performance ranged from > 1.6 to > 20 for both types of derivatives. Since preliminary data indicated that benzylamide derivatives of 2-PC displace [3H]1-[1-(2-thienyl)-cyclohexyl]piperidine (TCP) binding to the phencyclidine (PCP) site of the N-methyl-D-aspartate (NMDA) receptor in the micromolar range and such low affinity uncompetitive antagonists of the NMDA receptor-associated ionophore have been shown to be effective anticonvulsants with low neurological toxicity, the 2-PC derivatives were evaluated in rat brain homogenates for binding affinity to the PCP site. Although all compounds inhibited [3H]TCP binding, a clear correlation between pharmacological activity and binding affinity was not apparent. Select compounds demonstrated minimal ability to protect against pentylenetetrazol-, 4-aminopyridine- and NMDA-induced seizures in mice. Corneal and amygdala kindled rats exhibited different sensitivities to both valproic acid and the nonsubstituted 2-PC benzylamide, suggesting a difference in these two models. Enantiomers of the alpha-methyl substituted benzylamide of 2-PC showed some ability to reduce seizure severity in amygdala kindled rats.