A Homology Based Model and Virtual Screening of Inhibitors for Human Geranylgeranyl Transferase 1 (GGTase1)

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Title	A Homology Based Model and Virtual Screening of Inhibitors for Human Geranylgeranyl Transferase 1 (GGTase1)
Authors	Mallikarjuna Thippanna¹†, Parasuraman Aiya Subramani²†, Dakshayani Lomada³, Venkata Ramireddy Narala² & Madhava C Reddy¹*
Affiliation	¹Department of Biotechnology and Bioinformatics, ²Department of Zoology, ³Departments of Genetics and Genomics, Yogi Vemana University, Kadapa, Andhra Pradesh, India-516 003
Email	cmadhavareddy@gmail.com; *Corresponding author
Article Type	Hypothesis
Date	Received November 24, 2013; Accepted November 25, 2013; Published December 06, 2013
Abstract	Protein prenylation is a post translational modification that is indispensable for Ras–Rho mediated tumorigenesis. In mammals, three enzymes namely protein farnesyltransferase (FTase), geranylgeranyl transferase1 (GGTase1), and geranylgeranyl transferase2 (GGTase2) were found to be involved in this process. Usually proteins of Ras family will be farnesylated by FTase, Rho family will be geranylgeranylated by GGTase1. GGTase2 is exclusive for geranylgeranylating Rab protein family. FTase inhibitors such as FTI-277 are potent anti-cancer agents in vitro. In vivo, mutated Ras proteins can either improve their affinity for FTase active site or undergo geranylgeranylation which confers resistance and no activity of FTase inhibitors. This led to the development of GGTase1 inhibitors. A well-defined 3-D structure of human GGTase1 protein is lacking which impairs its in silico and rational designing of inhibitors. A 3-D structure of human GGTase1 was constructed based on primary sequence available and homology modeling to which pubchem molecules library was virtually screened through AutoDock Vina. Our studies show that natural compounds Camptothecin (-8.2 Kcal/mol), Curcumin (-7.3 Kcal/mol) have higher binding affinities to GGTase-1 than that of established peptidomimetic GGTase-1 inhibitors such as GGTI-297 (-7.5 Kcal/mol), GGTI-298 (-7.5 Kcal/mol), CHEMBL525185 (-7.2 Kcal/mol).
Keywords	Prenylation, GGTase1, Rho, Auto dock, Camptothecin.
Citation	Thippanna et al. Bioinformation 9(19): 973-977 (2013)
Edited by	P Kangueane
ISSN	0973-2063
Publisher	Biomedical Informatics
License	This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.