The Rational of Catalytic Activity of Herpes Simplex Virus Thymidine Kinase

Abstract

Pharmacological interactions are useful for understanding ligand binding mechanisms of a therapeutic target. These interactions are often inferred from a set of active compounds that were acquired experimentally. Moreover, most docking programs loosely coupled the stages (binding-site and ligand preparations, virtual screening, and post-screening analysis) of structure-based virtual screening (VS). An integrated VS environment, which provides the friendly interface to seamlessly combine these VS stages and to identify the pharmacological interactions directly from screening compounds, is valuable for drug discovery. We developed an easy-to-use graphic environment, i GEMDOCK, integrating VS stages (from preparations to post-screening analysis). For post-screening analysis, i GEMDOCK provides biological insights by deriving the pharmacological interactions from screening compounds without relying on the experimental data of active compounds. The pharmacological interactions represent conserved interacting residues, which often form binding pockets with specific physico-chemical properties, to play the essential functions of a target protein. Our experimental results show that the pharmacological interactions derived by i GEMDOCK are often hot spots involving in the biological functions. In addition, i GEMDOCK provides the visualizations of the protein-compound interaction profiles and the hierarchical clustering dendrogram of the compounds for post-screening analysis. We have developed i GEMDOCK to facilitate steps from preparations of target proteins and ligand libraries toward post-screening analysis. i GEMDOCK is especially useful for post-screening analysis and inferring pharmacological interactions from screening compounds. We believe that i GEMDOCK is useful for understanding the ligand binding mechanisms and discovering lead compounds. i GEMDOCK is available at http://gemdock.life.nctu.edu.tw/dock/igemdock.php .