Combining X-ray, Fragment Screening and Chemi-Informatics to Discover New Drugs

There has been a dearth of innovation and funding for early stage drug discovery and as a consequence the number of new drugs being approved has been decreasing in spite of more spending on development by drug companies. A new screening method fragment-based screening (FBS) which utilizes three-dimensional X-ray structures to find novel, custom-built inhibitors has led to several new drug candidates recently and has sparked interest in FBS throughout the industry. At ActiveSight we have built a technology platform that combines high-throughput X-ray structure determination, combinatorial chemistry automated FBS and chemi-informatics approaches to rapidly invent new and novel inhibitors. An example will be shown using the cancer target Hsp90. We have recently begun looking into novel methods for detecting fragment binding and have begun working with PARC on its nano-calorimeter, which shows a lot of promise as a pre-screen for FBS.

Presenter(s)

Dr. McRee is founder and President of ActiveSight, the drug discovery division of Rigaku Americas Corporation located in San Diego. He is widely known as an expert in protein crystallography and crystallographic software. He received his Ph.D. from Duke University in 1984 and joined The Scripps Research Institute in La Jolla where he ran an active program in the structure and function of metalloproteins, including doing the structure of the first microsomal P450. In 1993 he started Molecular Images, a molecular graphics software company that was acquired by Rigaku Americas in 2004. In 2000 he joined Syrrx, a drug discovery company to build their high throughput protein structure facilities. While at Syrrx he led a team that solved over 90 novel protein structures and hundreds of co-crystal structures which ultimately led to a type II diabetes drug IND in just 18 months. In 2003 he founded ActiveSight with other Syrrx scientists with funding from Rigaku. He remains an adjunct professor of Molecular Biology at Scripps and is a visiting professor of Sichuan University.