Homology modelling and docking studies of FGFR3 protein to search most effective drug against achondroplasia.
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Date
2010-08
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Abstract
The present investigation was carried out with the aim of modeling the 3D
structure of FGFR3 protein and predicting the most effective drug using SU5402 and its
analogues. FGFR3 protein, responsible for long bone growth, causes Achondroplasia in H.
sapiens when it becomes mutated. When mutated, the dimmer of FGFR3 stabilizes without
interacting with its ligand results in constitutive activation of downstream pathway and inhibits
the bone growth. No known structure of FGFR3 was available. The 3D modeling of FGFR3 was
done using Robetta server and from the various model predicted, model 5 was selected as the
best model after evaluating the models using PROCHECK. . The total number of residues in
selected model was found as: 589 (86.5%) residues in most favored region, 84 (12.3%) in
additional allowed region, 8 (1.2%) in generously allowed region and 0 (0.0%) in disallowed
region of the Ramachandran plot. Three analogues were constructed by using the existing
FGFR3 specific inhibitor SU5402. Receptor-analogue interaction study was performed in
FlexX3 docking software. Ligand 3 (IUPAC Name: 3-{2-[Z)-(4-hydroxy-2-oxo-1,2-dihydro-3Hindol-
3-ylidene) methyl]-4-oxo-4,5-dihydro-1H-pyrrol-3-yl} propanoic acid) was showing the
best binding energy (-10.458 KJ/Mol) that can be predicted the most effective inhibitor for
FGFR3. It should be noted that these predicted data should be validated using suitable assays for
further consideration.
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Keywords
FlexX3, FGFR3, in silico, ligands, Robetta
Citation
Chauhan Nutan, Ahmad Faizan, Siddiqui M A, Amir Asad, Singh Priyansha, Sahu Sarika. Homology modelling and docking studies of FGFR3 protein to search most effective drug against achondroplasia. International Journal of Applied Biology and Pharmaceutical Technology. 2010 Aug-Oct; 1(2): 329-338.