RESUMO
AIM: To investigate the influence of alterations in vitamin K (K1, K2 and K3) in modulating warfarin dose requirement. PATIENTS & METHODS: Reverse phase HPLC to determine the plasma vitamin K; PCR-RFLP to detect polymorphisms; and the neuro-fuzzy model to predict warfarin dose were used. RESULTS: The developed neuro-fuzzy model showed a mean absolute error of 0.000024 mg/week. CYP2C9*2 and CYP2C9*3 mediated warfarin sensitivity was observed when vitamin K is in high and low tertiles, respectively. VKORC1-1639G>A exhibited warfarin sensitivity in all combinations. Higher vitamin K1 was observed in CYP4F2 V433M polymorphism. The requirement of warfarin is low in GGCX 8016 GG genotype compared with GA and AA genotypes. CONCLUSION: Vitamin K profile along with genetic testing ensures precision in warfarin dose optimization.
Assuntos
Anticoagulantes/administração & dosagem , Anticoagulantes/farmacologia , Lógica Fuzzy , Varfarina/administração & dosagem , Varfarina/farmacologia , Adolescente , Adulto , Idoso , Povo Asiático , Criança , Feminino , Variação Genética/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Polimorfismo Genético/genética , Vitamina K/metabolismo , Adulto JovemRESUMO
To develop a potential inhibitor for glutamate carboxypeptidase II (GCPII) effective against all the eight common genetic variants reported, PyMOL molecular visualization system was used to generate models of variants using the crystal structure of GCPII i.e. 2OOT as a template. High-throughput virtual screening of 29 compounds revealed differential efficacy across the eight genetic variants (pIC50: 4.70 to 10.22). Pharmacophore analysis and quantitative structure-activity relationship (QSAR) studies revealed a urea-based N-acetyl aspartyl glutamate (NAAG) analogue as more potent inhibitor, which was effective across all the genetic variants of GCPII as evidenced by glide scores (-4.32 to -7.08) and protein-ligand interaction plots (13 interactions in wild GCPII). This molecule satisfied Lipinski rule of five and rule of three for drug-likeliness. Being a NAAG-analogue, this molecule might confer neuroprotection by inhibiting glutamatergic neurotransmission mediated by N-acetylated alpha-linked acidic dipeptidase (NAALADase), a splice variant of GCPII.
Assuntos
Simulação por Computador , Glutamato Carboxipeptidase II/antagonistas & inibidores , Neuroproteção/efeitos dos fármacos , Inibidores de Proteases/análise , Inibidores de Proteases/farmacologia , Variação Genética , Glutamato Carboxipeptidase II/química , Ligantes , Modelos Moleculares , Inibidores de Proteases/química , Relação Quantitativa Estrutura-AtividadeRESUMO
AIM: To evaluate the impact of CYP2C9*2 and CYP2C9*3 variants on binding and hydroxylation of warfarin. MATERIALS & METHODS: Multiple linear regression model of warfarin pharmacokinetics was developed from the dataset of patients (n = 199). Pymol based in silico models were developed for the genetic variants. RESULTS: CYP2C9*2 and CYP2C9*3 variants exhibited high warfarin/7-hydroxywarfarin (multiple linear regression model), dose-dependent disruption of hydrogen bonds with warfarin, dose-dependent increase in the distance between C7 of S-warfarin and Fe-O of CYP2C9, dose-dependent decrease in the glide scores (in silico). CONCLUSION: CYP2C9*2 and CYP2C9*3 variants result in disruption of hydrogen bonding interactions with warfarin and longer distance between C7 and Fe-O thus impairing warfarin 7-hydroxylation due to lower binding affinity of warfarin. Original submitted 7 May 2014; Revision submitted 30 October 2014.
