Computational assessment of the binding modes of the first VHL-recruiting PROTACs designed for oncogenic KRasG12C

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F25%3A50022061" target="_blank" >RIV/62690094:18470/25:50022061 - isvavai.cz</a>

Result on the web

<a href="https://pubs.rsc.org/en/Content/ArticleLanding/2025/NJ/D4NJ03612C" target="_blank" >https://pubs.rsc.org/en/Content/ArticleLanding/2025/NJ/D4NJ03612C</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/D4NJ03612C" target="_blank" >10.1039/D4NJ03612C</a>

Result language

angličtina

Original language name

Computational assessment of the binding modes of the first VHL-recruiting PROTACs designed for oncogenic KRasG12C

Original language description

A computational investigation was employed to better understand the engagementmechanism for the formation of ternary complexes involving VHL-recruiting PROTACs designedfor oncogenic KRasG12C. Rounds of protein-protein docking followed by conformational searchesenabled the prediction of the most likely ternary complexes for each PROTAC, which werefurther validated through rounds of MD simulations. The methodology was applied to sixPROTAC molecules (LC1 - LC6) that were designed, synthesized, tested in cell assays, andreported in the literature. These control systems included five different linker sizes and werederived from the KRasG12C covalent ligand MRTX849 and the VHL ligand 3. Our results suggestthat these compounds are capable of engaging KRasG12C and VHL, forming dynamically stableternary complexes under a predominant binding mode. It was also observed that KRasG12C andVHL exhibit similar dynamic behaviors for binding the PROTAC versus the individual ligandwarheads with no linker. Our findings reinforce the concept that this methodology can serve asa powerful tool for designing structures and prioritizing compounds for further synthesis andbiological evaluation.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30104 - Pharmacology and pharmacy

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

New journal of chemistry

ISSN

1144-0546

e-ISSN

1369-9261

Volume of the periodical

49

Issue of the periodical within the volume

5

Country of publishing house

GB - UNITED KINGDOM

Number of pages

11

Pages from-to

1596-1606

UT code for WoS article

001390051900001

EID of the result in the Scopus database

2-s2.0-85214568158