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Title: Structure-Based Design of RAGE/DIAPH1 Interaction Inhibitors: Targeting the Novel Intracellular Signalling Axis in Neurodegeneration

Study program: Biomedical Technology and Bioinformatics

Supervisor: doc. Ing. Mgr. Karel Sedlář, PhD (Sudeep Roy, PhD)

Topic description:

The receptor for advanced glycation end products (RAGE) plays a pivotal role in mediating neuroinflammation associated with Alzheimer’s disease and neurodegeneration through both extracellular interactions (AGE binding) and intracellular signaling pathways. Recent findings indicate that the cytoplasmic tail of RAGE directly interacts with diaphanous-related formin-1 (DIAPH1), triggering a crucial signaling cascade that results in cytoskeletal rearrangement, NF-κB activation, and the production of reactive oxygen species (ROS). While traditional RAGE antagonists, such as Azeliragon, focus on inhibiting extracellular AGE interactions, their clinical success has been limited. In contrast, the intracellular RAGE-DIAPH1 axis presents an untapped therapeutic opportunity. This project harnesses structure-based computational drug design techniques, including molecular dynamics simulations, MM-PBSA/MM-GBSA binding free energy calculations, and QSAR modeling, to thoughtfully develop novel DIAPH1-RAGE antagonists. Promising lead compounds will undergo validation through cellular assays (measuring ROS and MAPK signaling), followed by in vivo evaluations in STZ-induced Alzheimer’s disease models. This innovative approach zeroes in on a well-validated yet underexplored pathway, holding significant therapeutic promise for treating neurodegenerative diseases.

Your task:

  • Conduct original research leading to a dissertation or thesis.

  • Become an independent researcher with advanced skills in research techniques and

project management.

  • Engagement with the academic community, presenting at conferences and publishing.

  • Enhance knowledge and skills in leadership, mentoring, and teaching.

  • Build a professional profile through networking and skill acquisition for career aspirations.

Requirements:

  • Strong educational background (Master’s degree) in Bioinformatics/Cheminformatics.

  • Proficient in cheminformatics tools like molecular docking, Simulations, QSAR and pharmacophores

  • Demonstrates strong written and verbal communication skills for research publication and teamwork.

We offer:

  • Molecular Operating Environment (MOE), Schrödinger Suite (Glide, Maestro, Desmond) for drug discovery.

  • Collaborating across biology, pharmacology, and computer science.

Relevant publications:

https://doi.org/10.1002/pro.70240

https://doi.org/10.1038/s41598-025-01271-0

https://doi.org/10.1021/acschemneuro.5c00112

For more information about this topic please contact Sudeep Roy, roy@vut.cz

Application portal: https://www.vut.cz/eprihlaska/

Application deadline: April 30, 2026

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