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By Shona Sedlock

Shona Sedlock-finalDrug discovery takes too long (10 to 15 years) and the costs are too high ($4 to $11 billion) for it to be a sustainable part of our healthcare. Discovery and development must be cheaper, faster, and more reliable. Computer-aided modeling using Accelrys has shown time and time again that novel and lead compounds can be identified. These compounds can also be modified structurally for improved bioactivity and selectivity. Because this bench work can be done without ever setting a foot in a lab, the amount of cost and time saved is staggering.

While scientists have previously been skeptical about using computers to aid in drug design, the top 10 pharmaceutical companies currently use Accelrys Biovia for that very purpose. Drugs interact with their receptors by either blocking or stimulating the activity of specific proteins in the body. By beginning with a computerized structural model of the target protein (a PDB file) and libraries of chemical compounds, an evaluation can be made of the ligand-receptor interactions.


Crystal Structure


Docked Ligand

For example, the dysregulation of the epigenetic enzyme called coactivator-associated arginine methyltransferase 1 (CARM1) has been shown to contribute to the onset and progression of breast and prostate cancers. Using the crystal structure of CARM1 in complex with its current top inhibitor (CMPD-2) as a positive control (Fig. 1), it provides a model for downstream screening of over 75,500 compounds using the Accelrys Discovery Suite 4.5. Validation studies of the Accelrys docking algorithms have been previously evaluated across eight GlaxoSmithKline targets to assess both the accuracy in reproducing the binding mode of the ligand and retrieval of active compounds. Accelrys retrieved at least 20% of the active compounds in the top 10% of screened ligands. This research abstract, titled “The Search for Novel Inhibitors of Coactivator-Associated Arginine Methyltransferase 1” is being presented at the 2015 AAPS National Biotechnology Conference.

Screening vast libraries of compounds in vitro could take a lifetime to identify important new therapies, but computer modeling has the capacity to expedite drug discovery while significantly decreasing cost and time.


Figure 1. Top pose of CMPD-2 docked into CARM1 (2Y1X) using Accelrys® recapitulates the crystal structure. [Please click for full size.]

Shona Sedlock is a third year graduate student in the Faculty of Pharmaceutical Sciences at the University of British Columbia in Vancouver, Canada. She is currently using Accelrys® to conduct a high-throughput screening of novel inhibitors of coactivator-associated arginine methyltransferase 1 (CARM1) which has been shown to contribute to the onset and progression of breast and prostate cancers.