We are currently using upon virtual high-throughput screening (vHTS) system, which we have developed, to identify new lead compounds that will be further developed into drug candidates. We discovered that it is relatively straightforward to use in silico docking methods for a small number of compounds (<100) to the active site of an target receptor. However, it is very difficult to perform a large-scale screen, since millions of compounds are involved and hundreds of millions of data are produced that must be solved and evaluated. To this end we have developed a vHTS system that is straightforward to use and allows easily select of compounds and for the storage of data in databases for easy analysis of the results. The vHTS system can identify inhibitor structures that have no resemblance to the natural substrates or effectors, thus supplying a novel pool of structures that may become potential therapeutics.

We are using the vHTS system to develop inhibitors of aspartate transcarbamoylase (ATCase) and dihydroorotase (DHOase) in pyrimidine nucleotide metabolism and IMP dehydrogenase (IMPDH) and hypoxanthine-guanine phosphoryltransferase (HGPRT) in purine nucleotide metabolism. These enzymes have been selected because inhibitors of these enzymes have the potential to be anti-proliferative, anti-viral, and/or anti-malarial agents. The identification of these compounds by vHTS, in vitro functional studies and our ability to rapidly determine X-ray structures of enzyme•inhibitor complexes is a powerful combination with which to identify new inhibitors, and also ascertain their mode of action.  In total this project provides an opportunity to investigate novel inhibitors of purine and pyrimidine nucleotide metabolism, their mode of action, the mechanisms of the enzymes involved, and to offer insights for the design of new, more potent, inhibitor compounds.

Docking Software Current in Use:

AutoDock3

DOCK6

SURFLEX

GOLD