FOCUSBiochemistrypostdoctoral fellow and the first author ofthe study published in Science Signaling.Alternatively, virtual screenings usestructural biological information tocreate docking sites on a desired protein.Then, simulations can dock millions ofcompounds to test their interactions.Both screening methods have theirbenefits and drawbacks. Physicalscreening requires a significant amountof protein, an optimized experiment,and is also more expensive and timeintensive than computational methods.However, when you get a hit, youknow the compound is an inhibitor.On the other hand, computationalscreenings require researchers to havean idea of the protein structure andthe structure of the sites where smallmolecules can interact. After conductingcomputational models, researchers arerequired to eventually physically testthe compounds with the most promise.A positive is not necessarily guaranteedto be an inhibitor, and the highest hitrates are still fairly low. With insufficientinformation about docking sites onMKP5 for computational screenings, theresearch team opted to conduct physicalscreenings. The screening tests revealedthat a molecule, denoted by Compound1, showed promise in inhibiting MKP5.The How’s and the Why’sWith initial screenings showing theinhibitory properties of Compound 1,Bennett’s team wanted to find out howthe molecule interacts with MKP5.Understanding the molecular interactionsbetween MKP5 and Compound 1 requiredacquiring a crystal structure—a repeatedlattice of stable protein interactions—of the two interacting molecules, whichwould help researchers determine thestructure of the proteins and theirinteraction. “This was the first crystalstructure of an MKP in a complex with asmall molecule,” Gannam said. The lack ofprevious procedures for crystallographymeant that the team had to test out theMKP5-Compound 1 complex in solutionsof various combinations of buffers, saltsand precipitants. “It’s very idiosyncraticand there are not many set rules to follow,”Gannam said. Rounds and rounds ofscreening for crystallization were requiredto finally develop the crystal structure.The structure revealed that Compound1 fundamentally shifts the shape ofMKP5. Notably, a distinct allosteric siteon the protein shifts to interact withCompound 1. These shifts cause thevolume of the active site to decrease byeighteen percent. Analyzing the specificresidues which Compound 1 interactswith also showed its selectivity forMKP5 as opposed to other MKPs withinthe molecule family. Specifically, theresearch team showed that methionineand threonine residues on MKP5’sallosteric site were unique to it. Furthertests revealed that Compound 1 was lesseffective at inhibiting a mutated MKP5with altered methionine and threonineresidues. Thus, Compound 1 seems toselectively bind to MKP5 due to thesetwo residues.Moving to CellsSo far, research on Compound 1had been conducted outside of thecell. To make sure that Compound 1behaves predictably within a biologicalcontext, the team investigated theeffect of Compound 1 in mice cells.Since MKP5 inhibits MAPK andJNK, introducing Compound 1 wouldinhibit MKP5, therefore increasing thephosphorylation of MAPK and JNK. Notonly did Compound 1 increase MAPKABOUT THE AUTHORand JNK activities, it had no effect onother kinases such as ERK1/2, which isnot regulated by MKP5. These resultsshowed that even in a cellular context,Compound 1 seems to only inhibitMKP5, displaying the specificity that iscrucial for viability as a drug.What’s Next?Discovering Compound 1 representsthe crucial first step to developing atreatment for DMD. However, thereis still a long way to go to produce aviable drug. “Essentially, we have adrug development project to make acompound that is ideally highly potent,orally viable and fits the once-a-day pilltreatment,” Bennett said.Compound 1 may also have applicationsbeyond DMD. Compound 1 targets thepathway leading to tissue fibrosis or thethickening of scarring on tissue. Forexample, postoperative fibrosis is a type ofcomplication that occurs after surgeries,involving excess tissue scarring as a resultof the surgery. “Fibrosis accounts forforty-five percent of deaths worldwide invarious clinical presentations,” Bennettsaid. These include cardiac, lung, liver,and kidney fibrosis. Compound 1 canpotentially address these fibrosis diseasesand complications.The path to a workable drug requiresmeticulous and thorough work. It allowsfor innovations like Compound 1 to havethe potential to help millions. ■JENNY TANJENNY TAN is a sophomore in Saybrook majoring in Chemistry. She is from northern Virginia justoutside of Washington D.C. Outside of school, she likes baking and listening to music.THE AUTHOR WOULD LIKE TO THANK Zachary Gannam and Anton Bennett for their time andilluminating discussions about their research.FURTHER READINGAM;, M. (n.d.). Loss of MKP-5 promotes myofiber survival by activating STAT3/Bcl-2 signaling duringregenerative myogenesis. Retrieved November 26, 2020, from https://pubmed.ncbi.nlm.nih.gov/29047406/Bennett, A. M. (2019, January 01). MKP5 in Dystrophic Muscle Disease. Retrieved November 26, 2020,from https://grantome.com/grant/NIH/R01-AR066003-05Gannam, Z. T., Min, K., Shillingford, S. R., Zhang, L., Herrington, J., Abriola, L., . . . Bennett, A. M. (2020).An allosteric site on MKP5 reveals a strategy for small-molecule inhibition. Science Signaling, 13(646).doi:10.1126/scisignal.aba3043Zhang, W., & Liu, H. (n.d.). MAPK signal pathways in the regulation of cell proliferation in mammaliancells. Retrieved November 26, 2020, from https://www.nature.com/articles/729010518 Yale Scientific Magazine December 2020 www.yalescientific.org
ADJUSTINGQuantum CouplingFOCUSFORAchieving Imperative Error Correctionin Quantum ComputersBy Agastya RanaMISTAKESJust a couple of decades ago, afunctional quantum computer layfirmly in the realm of fantasy; theprospect of creating one was rifewith challenges both theoretical andpractical. Yet, given its unbounded potentialto solve problems that are unsolvable byconventional computers, scientists havepersevered, tirelessly chipping away at thebarriers that lay in their way. A recent paperin Nature from a team at Yale Universitysees us inch even closer towards this goal.They have successfully implemented acritical technique to extend the lifetimeof quantum data that could be used in aquantum computer.Image courtesy of Pixabay.www.yalescientific.orgDecember 2020 Yale Scientific Magazine 19
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