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.
RESUMEN
En este estudio se ha evaluado por medio de la metodología de acoplamiento molecular una serie de 5 ligandos borados, que son variantes de la molécula FL-078. Estas moléculas tienen actividad inhibitoria frente a la proteasa Mpro responsable de la replicación del SARS-CoV. Haciendo uso del programa SYBYL7.0 se optimizó el homodímero de la Mpro (código 1Q2W), y a través del software FlexX se hizo el acople molecular con el fin de escoger el confórmero más estable de los ligandos aril borados frente a la macromolécula Mpro, encontrándose que la estructura FL-166 fue la de mejor conformación. Los 5 ligandos aril borados tienen la propiedad de interaccionar con el grupo hidroxilo (OH) presente en los residuos tales como serinas, treoninas y tirosinas. Los resultados acople molecular muestran que el mejor acercamiento sobre la cavidad se da sobre el conjunto de treoninas 21, 24, 25 y 26, y no como se afirma en la literatura: que se da sobre el conjunto de serinas 139, 144 y 147.
In this study a set of 5 aryl boronic ligands which are variations of the FL-078 molecule were assessed. These molecules haveinhibitoryactivityagainstoftheMpro protease involved in the SARS-CoV replication. A homodimeroftheMpro(ID1Q2W) was optimized using the SYBYL7.0 package and through the FlexX software was calculated the molecular docking withthe aim of choose the most stable ligand front to Mpro macromolecule. Was found among the five boronic ligands that the best pose corresponded to the FL-166 structure. These molecules show interaction with the hydroxil group beared by aminoacid residues such as serines, threoni-nes and tyrosines. The docking calculation results presented here show that the best approaching over the cavity occur on the threonines set 21, 24, 25 and 26 instead of the set pointed out by other authors Serines 139, 144 and 147.
Neste estudo avaliou-se através da metodologia do acoplamento molecular uma serie de 5 ligandos contendo boro, que são variantes da molécula FL-078, estas moléculas têm atividade inibitória à protease Mpro responsável da replicação do SARS-CoV. Usando o programa SYBYL7.0 se otimizou o homodímero da Mpro (código 1Q2W), e através do software FlexX se realizou o acoplamento molecular com a finalidade de escolher o confórmero mais estável dos ligandos aril borados frente à macromolécula Mpro. Encontrando-se que a estrutura FL-166 foi a de melhor conformação. Os 5 ligandos aril borados têm a propriedade de interagir com o grupo hidro-xila (OH) presente nos resíduos tais como serinas, treoninas e tirosinas. Os resultados de acoplamento molecular mostraram que a melhor aproximação sobre a cavidade ocorre sobre o conjunto de treoninas 21, 24, 25 y 26 e não como se afirma na literatura que se da sobre o conjunto de serinas 139, 144 y 147.
RESUMEN
BACKGROUND: We have evaluated the analytical performance of SureStep Flexx (Johnson and Johnson, USA) which can report the plasma equivalent glucose test results and be connected to the hospital information networks, following ISO15197 analytic procedure for glucometer for the first time. METHODS: Adopting the guidelines of ISO15197, we measured the precision of ten glucometers from their repeatability and intermediate precision, and determined the accuracies of the glucometer, comparing to those of GEM Premier 4000 (Instrumentation Laboratory, USA). In addition, the guidelines of CLSI EP9-A2 and EP6-A were applied to correlate between data of glucometer and those of laboratory reference method by TBA-200FR (Toshiba Medical Systems, Japan) and to examine its linearity of glucose concentrations measured by SureStep Flexx. We used the clinical specimens and commercial control materials. RESULTS: Repeatabilities and intermediate precisions of those glucometers were 4.0-7.3%, and 4.3-6.2%, respectively. When glucose levels are under 75 mg/dL, the difference between results of those meters and the reference values were within +/-6 mg/dL. However when glucose levels are over 75 mg/dL, those differences were within +/-12.7%. These results were acceptable for the ISO15197 criteria in all glucose concentrations. The glucose concentrations showed the clinically relevant linearity in the range from 36 mg/dL to 491 mg/dL. Moreover, Error Grid Analysis showed that all glucose results were in "zone A", which means that these values were clinically accurate. CONCLUSIONS: This study showed that SureStep Flexx can provide reliable results for patients and clinicians to manage the diabetes mellitus, satisfying the ISO15197 criteria.