Synthon-Based Approach Improves Compound Screening

Researchers at the University of Southern California have created a process that reportedly increases the chances of finding effective drugs in a fraction of the time and at significantly less expense than current methods of drug discovery. Their new technology, called V-SYNTHES, is described in a recent Nature paper.

The team’s screening approach bypasses the library size problem that has hampered drug discovery by never having to build the full library. Instead, they work directly with the synthons, the virtual building blocks of the REAL Space library, to efficiently puzzle together the best molecules that fit the target.

V-SYNTHES is short for virtual synthon hierarchical enumeration screening. According to the team, it uses a fraction of the time and computing resources compared to other algorithms for virtual screening of REAL Space libraries. Instead of screening billions of fully pre-built molecules, V-SYNTHES starts by sifting through the much smaller library of synthons to find those that fit some part of the protein’s target pocket. Synthons with a good match in one part of the pocket are then “clicked” together with other synthons that may fit the other part.  

Repeating this process by adding pieces allows the researchers to build complete molecules and check their fit in the target pocket step by step, greatly facilitating the search for effective drugs.

To test V-SYNTHES, the team first focused on cannabinoid receptors. Searching through synthon libraries developed by the chemical company Enamine, V-SYNTHES was more than 5,000 times faster than standard algorithms at finding drug-like molecules that could selectively target cannabinoid receptors. Further, when the predicted drug candidates were synthesized and then tested in the lab, the number that actually worked—meaning those that effectively bound and blocked the cannabinoid receptors—was twice that of the candidates suggested by standard search algorithms.