Article ; Online: CSC01 shows promise as a potential inhibitor of the oncogenic G13D mutant of KRAS: an in silico approach.
2023 Volume 55, Issue 12, Page(s) 1745–1764
Abstract: About 30% of malignant tumors include KRAS mutations, which are frequently required for the development and maintenance of malignancies. KRAS is now a top-priority cancer target as a result. After years of research, it is now understood that the ... ...
| Abstract | About 30% of malignant tumors include KRAS mutations, which are frequently required for the development and maintenance of malignancies. KRAS is now a top-priority cancer target as a result. After years of research, it is now understood that the oncogenic KRAS-G12C can be targeted. However, many other forms, such as the G13D mutant, are yet to be addressed. Here, we used a receptor-based pharmacophore modeling technique to generate potential inhibitors of the KRAS-G13D oncogenic mutant. Using a comprehensive virtual screening workflow model, top hits were selected, out of which CSC01 was identified as a promising inhibitor of the oncogenic KRAS mutant (G13D). The stability of CSC01 upon binding the switch II pocket was evaluated through an exhaustive molecular dynamics simulation study. The several post-simulation analyses conducted suggest that CSC01 formed a stable complex with KRAS-G13D. CSC01, through a dynamic protein-ligand interaction profiling analysis, was also shown to maintain strong interactions with the mutated aspartic acid residue throughout the simulation. Although binding free energy analysis through the umbrella sampling approach suggested that the affinity of CSC01 with the switch II pocket of KRAS-G13D is moderate, our DFT analysis showed that the stable interaction of the compound might be facilitated by the existence of favorable molecular electrostatic potentials. Furthermore, based on ADMET predictions, CSC01 demonstrated a satisfactory drug likeness and toxicity profile, making it an exemplary candidate for consideration as a potential KRAS-G13D inhibitor. |
|---|---|
| MeSH term(s) | Humans ; Proto-Oncogene Proteins p21(ras)/genetics ; Colorectal Neoplasms/pathology ; Mutation ; Molecular Dynamics Simulation |
| Chemical Substances | Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; KRAS protein, human |
| Language | English |
| Publishing date | 2023-07-27 |
| Publishing country | Austria |
| Document type | Journal Article |
| ZDB-ID | 1121341-3 |
| ISSN | 1438-2199 ; 0939-4451 |
| ISSN (online) | 1438-2199 |
| ISSN | 0939-4451 |
| DOI | 10.1007/s00726-023-03304-2 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
Full text online
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Zs.A 3490: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.