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3D structure generation, virtual screening and docking of human Ras-associated binding (Rab3A) protein involved in tumourigenesis

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Title 3D structure generation, virtual screening and docking of human Ras-associated binding (Rab3A) protein involved in tumourigenesis
 
Creator LODHI, SS
FARMER, R
SINGH, AK
JAISWAL, YK
WADHWA, G
 
Subject Rab3A
GTP
GOLD Docking
Tumourigenesis
SYNAPTIC-VESICLE FUSION
GTPASES
VALIDATION
EXOCYTOSIS
ALIGNMENT
SYNAPSES
EFFECTOR
SUBUNIT
CELLS
 
Description Rab3A is expressed predominantly in brain and synaptic vesicles. Rab3A is involved specifically in tethering and docking of synaptic vesicles prior to fusion which is a critical step in regulated release of neurotransmitters. The precise function of Rab3A is still not known. However, up-regulation of Rab3A has been reported in malignant neuroendocrine and breast cancer cells. In the present study, the structure of Rab3A protein was generated using MODELLER 9v8 software. The modeled protein structure was validated and subjected to molecular docking analyses. Docking with GTP was carried out on the binding site of Rab3A using GOLD software. The Rab3A-GTP complex has best GOLD fitness value of 77.73. Ligplot shows hydrogen bondings (S16, S17, V18, G19, K20, T21, S22, S31, T33, A35, S38, T39 and G65) and hydrophobic interacting residues (F25, F32, P34, F36, V37, D62 and A64) with the GTP ligands in the binding site of Rab3A protein. Here, the ligand molecules of NCI diversity set II from the ZINC database against the active site of the Rab3A protein were screened. For this purpose, the incremental construction algorithm of GLIDE and the genetic algorithm of GOLD were used. Docking results were analyzed for top ranking compounds using a consensus scoring function of X-Score to calculate the binding affinity and Ligplot was used to measure protein-ligand interactions. Five compounds which possess good inhibitory activity and may act as potential high affinity inhibitors against Rab3A active site were identified. The top ranking molecule (ZINC13152284) has a Glide score of -6.65 kcal/mol, X-Score of -3.02 kcal/mol and GOLD score of 64.54 with 03 hydrogen bonds and 09 hydrophobic contacts. This compound is thus a good starting point for further development of strong inhibitors.
 
Publisher SPRINGER
 
Date 2014-12-28T14:40:21Z
2014-12-28T14:40:21Z
2014
 
Type Article
 
Identifier MOLECULAR BIOLOGY REPORTS, 41(6)3951-3959
0301-4851
1573-4978
http://dx.doi.org/10.1007/s11033-014-3263-x
http://dspace.library.iitb.ac.in/jspui/handle/100/16777
 
Language English