Abstract
Deguelin is a major active ingredient and principal component in several plants and it is a potential molecule to target proteins of cancer cell signaling pathway. As a complex natural extract, deguelin interacts with various molecular targets to exert its anti-tumor properties at nanomolar level. It induces cell apoptosis by blocking anti-apoptotic pathways, while inhibiting tumor cell multiplication and malignant transformation through p27-cyclin-E-pRb-E2F1- cell cycle control and HIF-1alphaVEGF antiangiogenic pathways. In silico studies of deguelin and its derivatives is performed to explore interactions with Cyclin D1 and Cyclin E to understand the molecular insights of derivatives with the receptors. Deguelin and its derivatives are minimized by Avogadro to achieve stable conformation. All docking simulation are performed with AutoDockVina and virtual screening of docked ligands are carried out based on binding energy and number of hydrogen bonds. Molecular dynamics (MD) and Simulation of Cyclin D1 and Cyclin E1 is performed for 100 ns and stable conformation is obtained at 78 ns and 19 ns respectively. Ligands thus obtained from docking studies may be probable target to inhibit cancer cell signaling pathways.
Highlights
Cyclin D1 is an important regulator of cell cycle progression and can function as a transcriptional co-regulator[5]
Interaction of deguelin and its derivatives with cyclin D1 and cyclin E, to understand molecular insights in to cell cycle arrest
Deguelin and its 181 derivatives are energy minimized using Steepest Descent method and Universal Force Field (UFF) and all the minimized compounds are subjected to the docking calculations with cyclin D1 and cyclin E receptor
Summary
Cyclin D1 is an important regulator of cell cycle progression and can function as a transcriptional co-regulator[5]. Cyclin E-CDK2 catalytic activity is required to down-regulate p27 protein. Cyclin E-Cdk[2] deregulation leads to development of cancer[4]. Cell cycle abnormalities are important feature of the procession of human cancers. Deguelin has been found to regulate cell cycle in colon cancer cells by stimulating p27 expression[17]. Interaction of deguelin and its derivatives with cyclin D1 and cyclin E, to understand molecular insights in to cell cycle arrest. The effectiveness of deguelin can be enhanced through designing its derivatives by applying advanced computational approaches like molecular modeling, docking, dynamics and simulation for initial screening of leads. At different time step of simulation, conformational flexibility of a receptor alter its interaction with ligand[23], because convergence of amino acid pattern[24]
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