Protherics Plc

This paper describes the validation of a molecular docking method and its application to virtual database screening. The code flexibly docks ligand molecules into rigid receptor structures using a tabu search methodology driven by an empirically derived function for estimating the binding affinity of a protein-ligand complex. The docking method has been tested on 70 ligand-receptor complexes for which the experimental binding affinity and binding geometry are known. The lowest energy geometry produced by the docking protocol is within 2.0 A root mean square of the experimental binding mode for 79% of the complexes. The method has been applied to the problem of virtual database screening to identify known ligands for thrombin, factor Xa, and the estrogen receptor. A database of 10,000 randomly chosen "druglike" molecules has been docked into the three receptor structures. In each case known receptor ligands were included in the study. The results showed good separation between the predicted binding affinities of the known ligand set and the database subset.

Available data suggest that drugs should be delivered to a vascular lesion at a high concentration over an extended period of time to control vascular smooth muscle cell (VSMC) proliferation. This study was undertaken to formulate a paclitaxel, an antimicrotubule agent, into a biodegradable poly (ethylene oxide)-poly(lactide/glycolide) (PEO-PLGA) nanosphere as a sustained drug delivery system and to study its effects on VSMC in culture. The paclitaxel-loaded nanospheres (PT/NS), prepared by an emulsion-solvent evaporation method, had an average diameter of approximately 150 nm and showed a sustained release profile over 4 weeks. The PT/NS exhibited antiproliferative effects comparable to those observed with free paclitaxel. The cellular internalization of nanospheres was visualized using confocal fluorescence microscopy, and from a flow cytometry study the progressive cellular uptake profile, uptake inhibition at low temperature, and saturation uptake kinetics (concentration dependency) were observed. These suggest that (adsorptive) pinocytosis is a major uptake mechanism of the nanospheres. The sustained drug release profile and cellular internalization results suggest that nanospheres loaded with paclitaxel may potentially be used as an endocytizable, local sustained drug delivery system for the prevention of restenosis.

A review, with 3 references, and a discussion of the BioEngine, a complex of hardware, software, and data banks which provide a complete working environment for the anal. prediction, and design of biol. mols.