Computational Identification of Small Molecules that Restore Wild-Type-Like Functional Dynamics of A53T α-Synuclein
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2025
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| author | Functional Dynamics, Lab |
| author_facet | Functional Dynamics, Lab |
| contents | <p><strong>This work is the Main hipothesys we are pursuing in the ongoing simulation we have running on Super Computing Infrastructure, but we need MORE COMPUTING POWER, we have the pipeline ready for the advanced search of a molecule that instead of inhibit toxicity be able to reduce it and maintain the function of A53T modulated as WT. </strong></p> <p><strong>Our Lab is open to non-comercial non-profir scientific collaboration in search of the lead candidates, IF YOU OR YOUR ORGANIZATION HAVE ACESS TO ADVANCE COMPUTATION POWER and are interested in the result of this study please contact us.</strong></p> <p>Abstract<br>Disease-modifying therapies targeting α-synuclein aggregation have repeatedly failed to demon-strate clinical efficacy despite robust preclinical activity. Notably, the Phase 2 ORCHESTRA trial of minzasolmin (UCB0599) did not meet its clinical endpoints, highlighting a critical gap between aggregation inhibition and functional restoration. Here, we present a fully automated, high-throughput molecular dynamics (MD) pipeline designed to evaluate whether small molecules restore wild-type-like functional dynamics of α- synuclein carrying the A53T mutation, rather than merely blocking aggregation. Using multi- microsecond explicit-solvent simulations, advanced dynamical analyses, membrane interaction modeling, and a composite Functional Restoration Index (FRI), we have a MD-ML pipeline designed and implemented to identify compounds that reprogram conformational ensembles toward functional behavior. This work is shared exclusively for scientific discussion and collaboration, with no commercial intent and no claims regarding proprietary compounds.</p> <p> </p> <p>Lab website: <a title="functionaldynamicslab.org.yzz.me" href="functionaldynamicslab.org.yzz.me"><strong>functionaldynamicslab.org</strong>.yzz.me</a></p> <p>Collaboration email: <strong>functionaldynamicslab@proton.me</strong></p> <p><strong>Files for reproduction will be shared on request</strong></p> |
| format | Recurso digital |
| id | zenodo_https___doi_org_10_5281_zenodo_17981810 |
| institution | Zenodo |
| language | |
| publishDate | 2025 |
| publisher | Zenodo |
| record_format | zenodo |
| spellingShingle | Computational Identification of Small Molecules that Restore Wild-Type-Like Functional Dynamics of A53T α-Synuclein Functional Dynamics, Lab PD alpha-Synuclein alpha-Synuclein/biosynthesis alpha-Synuclein/analysis alpha-Synuclein/ultrastructure alpha-Synuclein/metabolism alpha-Synuclein/physiology alpha-Synuclein/pharmacokinetics alpha-Synuclein/toxicity MDS1 and EVI1 Complex Locus Protein/metabolism Molecular Diagnostic Techniques Molecular Docking Simulation Molecular Dynamics Simulation <p><strong>This work is the Main hipothesys we are pursuing in the ongoing simulation we have running on Super Computing Infrastructure, but we need MORE COMPUTING POWER, we have the pipeline ready for the advanced search of a molecule that instead of inhibit toxicity be able to reduce it and maintain the function of A53T modulated as WT. </strong></p> <p><strong>Our Lab is open to non-comercial non-profir scientific collaboration in search of the lead candidates, IF YOU OR YOUR ORGANIZATION HAVE ACESS TO ADVANCE COMPUTATION POWER and are interested in the result of this study please contact us.</strong></p> <p>Abstract<br>Disease-modifying therapies targeting α-synuclein aggregation have repeatedly failed to demon-strate clinical efficacy despite robust preclinical activity. Notably, the Phase 2 ORCHESTRA trial of minzasolmin (UCB0599) did not meet its clinical endpoints, highlighting a critical gap between aggregation inhibition and functional restoration. Here, we present a fully automated, high-throughput molecular dynamics (MD) pipeline designed to evaluate whether small molecules restore wild-type-like functional dynamics of α- synuclein carrying the A53T mutation, rather than merely blocking aggregation. Using multi- microsecond explicit-solvent simulations, advanced dynamical analyses, membrane interaction modeling, and a composite Functional Restoration Index (FRI), we have a MD-ML pipeline designed and implemented to identify compounds that reprogram conformational ensembles toward functional behavior. This work is shared exclusively for scientific discussion and collaboration, with no commercial intent and no claims regarding proprietary compounds.</p> <p> </p> <p>Lab website: <a title="functionaldynamicslab.org.yzz.me" href="functionaldynamicslab.org.yzz.me"><strong>functionaldynamicslab.org</strong>.yzz.me</a></p> <p>Collaboration email: <strong>functionaldynamicslab@proton.me</strong></p> <p><strong>Files for reproduction will be shared on request</strong></p> |
| title | Computational Identification of Small Molecules that Restore Wild-Type-Like Functional Dynamics of A53T α-Synuclein |
| topic | PD alpha-Synuclein alpha-Synuclein/biosynthesis alpha-Synuclein/analysis alpha-Synuclein/ultrastructure alpha-Synuclein/metabolism alpha-Synuclein/physiology alpha-Synuclein/pharmacokinetics alpha-Synuclein/toxicity MDS1 and EVI1 Complex Locus Protein/metabolism Molecular Diagnostic Techniques Molecular Docking Simulation Molecular Dynamics Simulation |
| url | https://doi.org/10.5281/zenodo.17981810 |