ABSTRACT

We present systemsDock, a web server for network pharmacology-based prediction and analysis, which permits docking simulation and molecular pathway map for comprehensive characterization of ligand selectivity and interpretation of ligand action on a complex molecular network. It incorporates an elaborately designed scoring function for molecular docking to assess protein–ligand binding potential. For large-scale screening and ease of investigation, systemsDock has a user-friendly GUI interface for molecule preparation, parameter specification and result inspection. Ligand binding potentials against individual proteins can be directly displayed on an uploaded molecular interaction map, allowing users to systemically investigate networkdependent effects of a drug or drug candidate. A case study is given to demonstrate how systemsDock can be used to discover a test compound’s multi-target activity. systemsDock is freely accessible at http://systemsdock.unit.oist.jp/.

INTRODUCTION

Drugs may interact with multiple molecules in the human body, and such drug action, known as polypharmacology, may be efficacious or deleterious for the treatment of disease. For example, -lactams exhibit antibacterial action principally by targeting multiple penicillin-binding proteins (1). Similarly, a multi-target strategy has advanced the treatment of neurodegenerative diseases (2). On the other hand, poor drug selectivity may increase therapeutic risks and negatively impact drug development because of unintended drug-target interactions. An example of this is the cardiotoxicity of kinase inhibitor Sunitinib (3). Identification of drug targets is therefore a critical stage of drug development (4,5).