 |
Targeted Protein Degradation (TPD) is an approach that is attracting substantial interest for modulating challenging drug
targets. A major class of TPDs are Proteolysis-Targeting Chimera protein degraders (PROTACs). PROTACs are heterobifunctional molecules where two ligands are joined by linker. One ligand recruits the target and the other recruits and binds an E3 ubiquitin ligase. This interaction induces ubiquitylation of the target and degradation by the ubiquitin-proteasome system, the PROTAC is then recycled.
The MolSoft ICM PROTAC modeling method:
- Start with structures of target protein and cereblon or VHL complexes with their respective binding ligands/moieties
- PROTAC molecule is modeled into first complex and then into second complex using ligands as templates
- Internal coordinate MC simulation sampling linker torsions optimizes tripartite complex
- Surrounding sidechains also flexible
- Resulting ensemble of low energy conformers is re-evaluated using scoring function optimized for protein-protein docking
|
Benchmark
At MolSoft's User Group Meeting, Dr. Evianne Rovers from the Structural Genomics Consortium presented a benchmarking study comparing ICM with other PROTAC modeling tools. The results showed that ICM outperformed other methods in accurately predicting near-native PROTAC ternary complexes and achieving lower RMSD values for docked PROTACs.
- Watch the User Group Meeting presentation here.
- Read the publication here.
ICM PROTAC Modeling Example from the NIH
A study published in RSC Medicinal Chemistry by Dr. Burke's lab at the NIH National Cancer Institute (NCI) explores the development of proteolysis-targeting chimeras (PROTACs) to selectively degrade tyrosyl-DNA phosphodiesterase 1 (TDP1). The paper, titled "Application of a Bivalent "Click" Approach to Target Tyrosyl-DNA Phosphodiesterase 1 (TDP1)," highlights the potential for PROTACs to enhance the efficacy of topoisomerase 1 (TOP1) inhibitors used in cancer therapy.
Using MolSoft ICM, the researchers modeled the ternary structure of a PROTAC complex, docking a lead imidazopyridine-based TDP1 inhibitor (compound 1b) with thalidomide to form a bivalent conjugate (compound 5h). The modeling results confirmed that the linker in 5h was optimally positioned, extending from the peptide-binding groove of TDP1 toward the CRBN binding site, supporting the intended PROTAC mechanism.
This study provides valuable insights into the structure-based design of TDP1-targeting PROTACs, paving the way for future therapeutic advancements.
- Read the full paper here.
Publications
PROTAC Pocket Analysis using MolSoft's ICM-PocketFinder Method
- Rovers E, Liu L, Schapira M. ProxyBind: A compendium of binding sites for proximity-induced pharmacology. Comput Struct Biotechnol J. 2022 Nov 8;20:6163-6171. doi: 10.1016/j.csbj.2022.11.010. PMID: 36420167; PMCID: PMC9674861.
PROTAC Modeling Benchmark
- Rovers E, Schapira M. Benchmarking Methods for PROTAC Ternary Complex Structure Prediction. J Chem Inf Model. 2024 Aug 12;64(15):6162-6173. doi: 10.1021/acs.jcim.4c00426. Epub 2024 Aug 1. PMID: 39087481.
- Rovers E, Schapira M. Methods for computer-assisted PROTAC design. Methods Enzymol. 2023;690:311-340. doi: 10.1016/bs.mie.2023.06.020. Epub 2023 Jul 21. PMID: 37858533.
| Watch a Webinar on PROTAC Modeling in ICM|
