CSC01 shows promise as a potential inhibitor of the oncogenic G13D mutant of KRAS: an in silico approach

• Published in: Amino acids 2023-12, Vol.55 (12), p.1745-1764
• Main Authors: Durojaye, Olanrewaju Ayodeji, Ejaz, Umer, Uzoeto, Henrietta Onyinye, Fadahunsi, Adeola Abraham, Opabunmi, Adebayo Oluwole, EKPO, Daniel Emmanuel, Sedzro, Divine Mensah, Idris, Mukhtar Oluwaseun
• Format: Article
• Language: English
• Subjects: Analytical Chemistry; Aspartic acid; Binding; Biochemical Engineering; Biochemistry; Biomedical and Life Sciences; Colorectal Neoplasms - pathology; Free energy; Humans; Inhibitors; K-Ras protein; Life Sciences; Malignancy; Molecular dynamics; Molecular Dynamics Simulation; Mutants; Mutation; Neurobiology; Original Article; Proteomics; Proto-Oncogene Proteins p21(ras) - genetics; Simulation; Stability analysis; Toxicity; Workflow
• ISSN: 0939-4451; 1438-2199
• DOI: 10.1007/s00726-023-03304-2

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.