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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

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

Název periodika

New journal of chemistry

ISSN

1144-0546

e-ISSN

1369-9261

Svazek periodika

49

Číslo periodika v rámci svazku

5

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

11

Strana od-do

1596-1606

Kód UT WoS článku

001390051900001

EID výsledku v databázi Scopus

2-s2.0-85214568158