New Drug Creation Method May Reduce Side Effects from Heart Disease Treatments

Drugs targeting allosteric binding sites may prevent side effects associated with heart medications.

Investigators in a recent study discovered a potential drug that could selectively counter heart disease of varying severity.

In a study published by the Proceedings of the National Academy of Sciences, a computational approach was used to sample proteins in their natural state of gyrating, bobbing, and weaving. Accelerated molecular dynamics (aMD) was employed to sample the multiple shapes and conformations a protein may go through in their natural state.

“The supercomputing power of Gordon, Comet, and Stampede allows us to run hundreds-of-nanosecond aMD simulations, which are able to capture millisecond timescale events in complex biomolecules,” said study first author Yinglong Miao, PhD.

Many current heart medications act on the M2 muscarinic acetylcholine receptors (M2 mAChRs), to decrease heart rate and reduce heart contractions. However, these drugs can potentially cause serious side effects, due to the location of the primary orthosteric binding site being on at least 4 receptor types in the body.

Molecular targets or allosteric binding sites are separate from the primary binding site, and have a more diverse genetic sequence than orthosteric binding sites, making it a target for selective drugs. The allosteric sites can fine tune the activation and the pharmacological profile of the target receptor, according to the study.

“Allosteric sites typically exhibit great sequence diversity and therefore present exciting new targets for designing selective therapeutics,” said study co-investigator J. Andrew McCammon, PhD.

Drug designers have also been searching for allosteric modulators to fine-tune treatments that bind to G protein-coupled receptors that are prevalent in up to half of all marketed drugs. Drugs that bind to G protein-coupled receptors lack specificity by targeting the orthosteric binding sites of receptors, and can result in side effects.

“The problem here is that molecules that bind to these allosteric sites have proven extremely difficult to identify using conventional high-throughput screening techniques,” Dr McCammon said.

In the study, investigators selected 38 lead compounds from a database, and used computer simulations to determine binding strength and receptor flexibility. They discovered approximately half of the compounds showed allosteric behavior, and a dozen showed strong affinity to the M2 mAChR binding site, the researchers wrote.

After further analysis, they discovered 2 that showed affinity and selectivity.

“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 wrote.

Additional research is needed to examine the chemical properties of the molecules, according to the study.

“This is just the beginning. We believe that it will be possible to apply our combined cutting-edge in silico and in vitro techniques to a wide array of receptor targets that are involved in some of the most devastating diseases,” said study co-lead investigator Celine Valant, PhD.