As with keys, the exact shape of a macrocycle matters. Build one with the right conformation and you may unlock a new cure.
Modeling realistic conformations is "one of the hardest parts" of macrocycle design, according to Vikram Mulligan, another lead author of the report. But thanks to the efficiency of the robotics-inspired algorithm, the team was able to achieve "near-exhaustive sampling" of plausible conformations at "relatively low computational cost."
The calculations were so efficient, in fact, that most of the work did not require a supercomputer, as is usually the case in the field of molecular engineering. Instead, thousands of smartphones belonging to volunteers were networked together to form a distributed computing grid, and the scientific calculations were doled out in manageable chunks.
With the initial smartphone number-crunching complete, the team pored over the results — a collection of hundreds of never-before-seen macrocycles. When a dozen such compounds were chemically synthesized in the lab, nine were shown to actually adopt the predicted conformation. In other words, the smartphones were accurately rendering molecules that scientists can now optimize for their potential as targeted drugs.
The team estimates the number of macrocycles that can confidently be used as starting points for drug design has jumped from fewer than 10 to over 200, thanks to this work. Many of the newly designed macrocycles contain chemical features that have never been seen in biology.
To date, macrocyclic peptide drugs have shown promise in battling cancer, cardiovascular disease, inflammation and infection. Thanks to the mathematics of robotics, a few smartphones and some cross-disciplinary thinking, patients may soon see even more benefits from this promising class of molecules.
Commentary by Ian Haydon, a doctoral student in biochemistry at the University of Washington. He is also a contributor at The Conversation, an independent source of news and views from the academic and research community.
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