Molecular docking and simulation of Curcumin with Geranylgeranyl Transferase1 (GGTase1) and Farnesyl Transferase (FTase).

,Parasuraman Aiya Subramani,Venkata Ramireddy Narala,R Dinakaran Michael,Madhava C Reddy,Department Of Zoology, Yogi Vemana University, Kadapa ,Dakshayani Lomada,Department Of Genetics And Genomics, Yogi Vemana University, Kadapa

doi:10.6026/97320630011248

Abstract

Protein prenylation is a posttranslational modification that is indispensable for translocation of membrane GTPases like Ras, Rho, Ras etc. Proteins of Ras family undergo farnesylation by FTase while Rho family goes through geranylgeranylation by GGTase1. There is only an infinitesimal difference in signal recognition between FTase and GGTase1. FTase inhibitors mostly end up selecting the cells with mutated Ras proteins that have acquired affinity towards GGTase1 in cancer microcosms. Therefore, it is of interest to identify GGTase1 and FTase dual inhibitors using the docking tool AutoDock Vina. Docking data show that curcumin (from turmeric) has higher binding affinity to GGTase1 than that of established peptidomimetic GGTase1 inhibitors (GGTI) such as GGTI-297, GGTI-298, CHEMBL525185. Curcumin also interacts with FTase with binding energy comparable to co-crystalized compound 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-amino-1-(1-methyl-1h-imidizol-5-yl)-ethyl]-benzonitrile (BNE). The docked complex was further simulated for 10 ns using molecular dynamics simulation for stability. Thus, the molecular basis for curcumin binding to GGTase1 and FTase is reported.

Highlights

Protein prenylation is a posttranslational modification that is indispensable for translocation of membrane GTPases like Ras, Rho, Ras etc
Though proven to be very good drugs with amazingly nil side effects, farnesyl transferase (FTase) inhibitors (FTI) failed to prevent tumor proliferation completely as some Ras isoforms like K-Ras-4B bind the enzyme more avidly than FTIs like L744,832, and FTI-277 or undergo alternative prenylation i.e. geranylgeranylation [7]
Rho family of GTPases belongs to Ras superfamily of proteins that are geranylgeranylated by GGTase1

Summary

Introduction

Protein prenylation is a posttranslational modification that is indispensable for translocation of membrane GTPases like Ras, Rho, Ras etc. Protein prenylation is an important posttranslational change in amino acid recognition sequence by these three modification through which naïve protein molecules are enzymes confirms that any given protein is prenylated with targeted to membranes. It helps in protein-protein only one of them. Though proven to be very good drugs with amazingly nil side effects, FTase inhibitors (FTI) failed to prevent tumor proliferation completely as some Ras isoforms like K-Ras-4B bind the enzyme more avidly than FTIs like L744,832, and FTI-277 or undergo alternative prenylation i.e. geranylgeranylation [7]. It becomes clear that an FTase-GGTase dual inhibitor may be of certain interest

Methods

Results

Conclusion