💊 Targeted Protein Degradation

Targeted Protein Degradation with Discovery Studio

Novel strategies for designing therapies do not appear often, and targeted protein degradation, TPD, is one of such fairly recent novel strategies.

Our customer C4 Therapeutics is actively developing this technique.

The company says:

Targeted protein degradation harnesses the cell’s innate capability to control protein levels to remove known drivers of disease.

TPD method marks a protein for destruction, most often by using a so-called degrader molecule. The process is based on generation of an intermediary ternary complex – target–degrader–ligase.

Target–degrader–ligase leads to a destruction of protein through a natural cellular process called ubiquitination. Degraders differ from inhibitors – they actually destroy target proteins rather than limiting their activity.

Quick Insights

A recent paper by C4 Therapeutics with BIOVIA’s Jodi Shaulsky combines experimental and computational tools to offer a workflow to provide rapidly accessible structural insights into degrader-induced protein–protein interfaces in solution.

The paper Structural Characterization of Degrader-Induced Ternary Complexes Using Hydrogen–Deuterium Exchange Mass Spectrometry and Computational Modeling: Implications for Structure-Based Design appeared in the ACS Chemical Biology journal.

Discovery Studio’s CHARMm was used to package protein-degrader complexes, and they were scored for complementarity using the protein-protein binding ZRANK scoring. This work creates an interesting template for TPD studies, using e.g. PROTAC® methodology.

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Victor Milman

BIOVIA, Dassault Systèmes
Senior Director of the Quantum Mechanics and Nanotechnology R&D Team, Victor Milman, Ph.D., joined BIOVIA in 1994 and currently serves as a senior fellow and manager of quantum mechanics and nanotechnology research and development team. He graduated from Moscow Institute of Physics and Technology and received his doctorate in solid state physics from The Ukrainian Academy of Sciences. His subsequent research at the Institute of Metal Physics in Kiev focused on development of first principles techniques for study of lattice properties of inorganic crystals. This work continued at the Cavendish Laboratory, Cambridge, where he was employed as a Research Associate for the SERC Collaborative Computational Project in electronic structure of solids. This activity in the group of Professor Heine and Professor Payne culminated in the public release of CASTEP, a revolutionary code for quantum-mechanical modelling of solids and surfaces. Milman further worked for a year as a visiting research fellow at the DOE Oak Ridge National Laboratory, concentrating on applications of CASTEP to physics of semiconductors, from modelling growth processes to study of extended defects. Victor Milman has 150 peer-reviewed publications with the h-index of 29, which reflects both productivity and high scientific impact of his research. His contributions include numerous conference presentations, co-supervision of doctorate students with University of Cambridge and with University College London, organization of meetings and symposia, regular refereeing of papers for the major journals in physics and chemistry.
Victor.MILMAN@3ds.com'

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