Studies on geraniol derivatives targeting KRASG12D gene of pancreatic ductal adenocarcinoma

AbstractKirsten rat sarcoma virus (KRAS) mutations are central to the molecular framework, which are present in 90% of Pancreatic Ductal Adenocarcinoma (PDAC) cases and play a pivotal role in pancreatic carcinogenesis. KRASG12D gene refers to a specific mutation in the KRAS gene of Pancreatic Ductal Adenocarcinoma where glycine at position 12 is substituted with aspartic acid. In this study, Gas Chromatography-Mass Spectrometry (GC MS) analysis was conducted to profile chemical components of geranium oil which is subjected to Lipinski, and ADME screening based on the parameters which elucidate their biological activity and pharmacokinetics, followed by molecular docking of screened geranyl derivatives to explore their potential as KRAS G12D inhibitors. In-silico prediction tools such as Lipinski Rule of Five, SwissADME, AutoDock Tools 1.5.7. OpenBabelGUI, PyMOL© Molecular graphics system, Discovery Studio Visualizer, the Protein-Ligand interaction profiler are used for ligand screening and molecular interaction analysis. The docking affinity and interacted amino acid residues of these docked compounds were compared with the docking affinity and interacted amino acid residues of MRTX1133, a known KRAS G12D inhibitor respectively to identify the suitable ligand. In-silico tools helped to identify the suitable ligand Neryl isobutyrate for further studies as it’s amino acid interaction (Val 9, Tyr 64, Met 72, Tyr 96, Ile 100, Val 103) with protein and binding energy (-7.61 kcal/mol) were most probably similar and close to the drug MRTX1133 (Control) respectively. These preclinical findings could generate increased interest in these compounds for the treatment of PDAC and elucidate the potential of KRASG12D-targeted medicine in this context as prospects for an enhanced treatment against PDAC.