Computing powerhouses discover new receptor binding sites in heart failure

An outline of a mouse heart

Current heart failure therapy is limited by serious side effects. Researchers have now designed a computational approach to characterize protein structures that are targets for heart failure drugs. The results may lead to better drug development: compounds that can subtly fine-tune the heart, without the side effects.

The study was a collaborative effort between two computing powerhouses based at UC San Diego and the University of Texas. The results were published in the Proceedings of the National Academy of Sciences (PNAS) earlier this week.

The researchers used a technique called accelerated molecular dynamics (aMD) that examines the different possible conformations a target protein goes through. The unprecedented computing power for this use allowed the researchers to run hundreds of parallel simulations, capturing millisecond timescale events in complex proteins. (More on aMD here.)

A common target of heart failure in the clinic is the M2 muscarinic acetylcholine (mACh) receptor. Although effective in reducing heart rate and force of contraction, improving life for patients, it can lead to major side effects in a subset of patients. Study co-investigator Andrew McCammon says this is due to the primary binding site of the receptor sharing a common genetic sequence with at least four other receptors, resulting in unwanted and off-target effects.

The researchers therefore looked for binding sites away from the primary binding site known as allosteric binding sites. By targeting these sites, it would be possible to fine-tune the behavior of the receptor, without altering inappropriate receptors.

"Allosteric sites typically exhibit great sequence diversity and therefore present exciting new targets for designing selective therapeutics," said McCammon in a statement. “The problem here is that molecules that bind to these allosteric sites have proven extremely difficult to identify using conventional high-throughput screening techniques."

Using their aMD technique, some 38 lead compounds were taken forward and tested for their in vitro behavior; half came out for having allosteric effects on the M2 mACh receptor binding site.

"To our knowledge, this study demonstrates for the first time an unprecedented successful structure-based approach to identify chemically diverse and selective GPCR allosteric modulators with outstanding potential for further structure-activity relationship studies," the researchers said in a statement.