Structure-Based Drug Design: A Key Technology for Drug Discovery in the Pharmaceutical Industry

Abstract

A drug discovery becomes increasingly harder under the situation such as a keen competition, a decrease of easy drug-targets, and a requirement of high-level safety and efficacy. In these conditions, Chugai pharmaceutical (a member of Roche group) actively utilizes a Structure-Based Drug Design (SBDD) technology and the information of the 3D structures of protein/ligand complexes during the drug discovery to increase the success rate and to obtain drugs with novel additional values. In this talk, two examples of SBDD will be introduced. Firstly, the discovery of a Pure Antagonist (PA) of Androgen Receptor (AR), which is a member of a Nuclear Hormone Receptor (NHR), for prostate cancer will be presented. Under the situation that no PA of AR was reported, the information of the 3D structures of NHR other than AR was used for the design of a PA of AR and the PAs were successfully obtained. The second example is the discovery of the inhibitors of Heat shock protein 90 (Hsp90) as an anti-cancer agent. In order to identify the active molecules, fragment screening approach and in silico screening approach using the 3D structure of Hsp90 were performed in parallel, and the in-vivo active Hsp90 inhibitors were obtained finally. These examples will show how SBDD is being applied at Chugai and clearly highlight the power of SBDD.