RESUMEN
The discovery of leptin has initiated a flurry of research into the molecular basis of weight control. In obese people levels of leptin found in the blood are normally very high and more than sufficient to suppress the appetite and increase the metabolism. This however does not happen and it is believed that obesity may be the result of a resistance to leptin. This suggests that the problem in these individuals may be related to a lack of binding of the leptin protein to its receptor. No known structure of leptin receptor is known. Therefore in present the present study we model the 3D structure of leptin receptor using MODELLER. This was done using the template GP130 of H. sapiens (PDB code: 1BQU). On the basic of results MODEL 6 was selected as the best model. The observed G-factors for the present model were -0.22 for dihedrals, -0.32 for covalent and overall -0.25. The MODEL 6 contains 88.7% of the residues in the most favored region, 11.3 % in the additional allowed and no single residue in generously allowed regions and disallowed region. The predicted model was further analyzed to locate the residues in the active sites those provide interactions with the ligand.
RESUMEN
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.