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Even though researchers observed that the a-syn protein accumulatedin the central nervous system of Parkinson's patients and in thosewith a related disorder called dementia with Lewy bodies several years ago, Tsigelny says that themodeling creates a significantly better understanding of the a-synprotein itself. The new modeling study precisely demonstrates how two -synproteins insert their molecular toes into a neuron's membrane,penetrate into it within just a few nanoseconds and immediatelyjoin together as a pair that in itself is not toxic, however, asmore a-syn proteins join, the key threshold is eventuallyoverstepped, which results in an accelerated polymerization into aring structure that perforates the membrane, which damages thecell. According to Tsigelny, it may require many ring structures toactually kill neurons, which are generally very durable. Eventhough the nerve cells may be able to repair dozens of ring-inducedperforations and are able to keep the pace with the a-syn assaultup to a certain point, they will however at some stage be overtakenby the rate of perforations, which results in a gradual appearanceof Parkinson's symptoms that becomes worse. Tsigelny explains: "We think we can create a drug that stops the -syn polymerizationat the point of non-propagating dimmers. By interrupting thepolymerization at this crucial step, we may be able to slow thedisease significantly." The experimental validation studies were based on 3-D models ofproteins, plus molecular dynamics simulations of the proteins,other modeling techniques and cell-culture experiments. Due to adeeper understanding of -syn polymerization in neurons, theresearchers now focus on gaining insight into how monomers of -syn stick to one another. In their pursuit of finding drugcandidates they will include molecules, which cause different a-synprotein conformations that are less inclined to stick together, asthis effect, even if small, could decrease symptoms. Pharmaceutical companies have used versions of this computationallyintensive approach that includes examining many possiblethree-dimensional arrangements of -syn dimers, trimmers andtetramers to develop drug candidates designed to bind to 'anchorresidues' or 'hot spots' within target proteins. Virtualexperiments of the theoretical ability of thousands of candidatedrugs binding to human proteins in the ever-expanding database ofknown 3-D protein structures are assessed by algorithms. Eventhough promising candidates have been discovered using thisapproach, they regularly fail in clinical trials. Tsigelny, a physicist who turned into a drug-designer explained: "Out of these failures we've come to appreciate that proteinschange their shapes so often that what would appear to be a primarydrug target may be present one nanosecond, gone the next, or itwasn't relevant in the first place." Tsigelny's approach takes advantage of classical drug-discoveryalgorithms, but adds additional analytical techniques to expand thesearch to include how a target protein's conformations change inresponse to the forces operating on the scale of molecules. He concludes: "Sometimes, the drug-discovery models, despite being 'nicelooking,' can be completely wrong. Scientists involved in drugdiscovery need to know when and to what extent to trust them. Evena slight shift in a cell's environment can profoundly change theinteractions of proteins with neighboring molecules. We think it'srealistically possible to design a drug to treat neurodegenerativediseases such as Parkinson's disease and other diseases like diabetes with a more fundamental understanding of the proteins involved inthose diseases." Written By Petra Rattue Copyright: Medical News Today Not to be reproduced without permission of Medical News Today Additional References Citations. We are high quality suppliers, our products such as China Custom Mailing Bags , China Cardboard Envelopes for oversee buyer. To know more, please visits Courier Envelopes.
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