2. Academic Validation
  3. Structure-Based Discovery of Active Pan-KRas Inhibitors Targeting G12D Mutants by Enhanced Sampling Simulations

Structure-Based Discovery of Active Pan-KRas Inhibitors Targeting G12D Mutants by Enhanced Sampling Simulations

  • J Phys Chem B. 2025 Sep 18;129(37):9283-9292. doi: 10.1021/acs.jpcb.5c01781.
Juan Zeng 1,  Li Li 2,  Chi Sun 2,  Shen Sheng 2,  Yuhua Tan 2,  Jian Chen 3,  Fei Xia 3,  Xianming Deng 2 4,  Xin Xu 5
Affiliations

Affiliations

  • 1 School of Biomedical Engineering, Guangdong Medical University, Dongguan 523808, China.
  • 2 State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
  • 3 Shanghai Engineering Research Center of Molecular herapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
  • 4 Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen 361003, China.
  • 5 State Key Laboratory of Porous Materials for Separation and Conversion, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, MOE Key Laboratory of Computational Physical Sciences, Department of Chemistry, Fudan University, Shanghai 200433, China.
PMID: 40905485 DOI: 10.1021/acs.jpcb.5c01781
Abstract

Ras is a node protein in the classic tumor signaling pathway known as RAS-RAF-MEK. Mutations in Ras are reported to occur in approximately 19% of human cancers. Among them, the G12D mutation is one of the most prevalent mutations found in Ras. In this study, we performed replica-exchange molecular dynamics (REMD) simulations on the KRas G12D mutant, revealing that its conformational space is remarkably different from that of wild-type KRas, particularly in State 1. Based on two specific conformations of the KRas G12D mutant, we screened an in-house molecular library. Two compounds, designated SS-3091 and SS-30125, were experimentally verified to have the strong inhibitory effects. MD simulations starting from the docked complexes revealed that SS-3091 and SS-30125 bind to the interaction interfaces of KRas and ARaf, destabilizing the ARaf·KRas complex. The Anticancer activities of SS-3091 and SS-30125 have been validated against the KRas G12D, G12C, G12V, and G12S mutants in various Cancer cells. All findings underscore the potential of SS-3091 and SS-30125 as very promising active pan-KRas inhibitors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-178042
    KRas Inhibitor
    Ras