DFT and molecular simulation validation of the binding activity of PDE[delta] inhibitors for repression of oncogenic k-Ras

• Published in: PloS one Vol. 19; no. 3
• Main Authors: Majrashi, Taghreed A, Sabt, Ahmed, Almahli, Hadia, El Hassab, Mahmoud A, Noamaan, Mahmoud A, Elkaeed, Eslam B, Hamissa, Mohamed Farouk, Maslamani, Abdalkareem Nael, Shaldam, Moataz A, Eldehna, Wagdy M
• Format: Journal Article
• Language: English
• Published: Public Library of Science 08.03.2024
• Subjects: Analysis; Density functionals; Evaluation; Guanosine triphosphatase; Health aspects; Molecular dynamics; Egypt
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0300035

The development of effective drugs targeting the K-Ras oncogene product is a significant focus in anticancer drug development. Despite the lack of successful Ras signaling inhibitors, recent research has identified PDE[delta], a KRAS transporter, as a potential target for inhibiting the oncogenic KRAS signaling pathway. This study aims to investigate the interactions between eight K-Ras inhibitors (deltarazine, deltaflexin 1 and 2, and its analogues) and PDE[delta] to understand their binding modes. The research will utilize computational techniques such as density functional theory (DFT) and molecular electrostatic surface potential (MESP), molecular docking, binding site analyses, molecular dynamic (MD) simulations, electronic structure computations, and predictions of the binding free energy. Molecular dynamic simulations (MD) will be used to predict the binding conformations and pharmacophoric features in the active site of PDE[delta] for the examined structures. The binding free energies determined using the MMPB(GB)SA method will be compared with the observed potency values of the tested compounds. This computational approach aims to enhance understanding of the PDE[delta] selective mechanism, which could contribute to the development of novel selective inhibitors for K-Ras signaling.