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Objective: Dabigatran Etexilate is an oral acting direct thrombin inhibitor used for prophylaxis of cardioembolic events in non-valvular atrial fibrillation patients. Genetic polymorphisms in hCES1 gene can significantly alter the conformations of the enzyme drug binding and impair the catalytic ability. Hence this study is performed to determine the effect of single nucleotide variations on dabigatran activation by hCES1. Methods: Energy minimization was performing using YASARA server. Dihedral angles of the modeled targets were visualized using Ramachandran Plot. We performed molecular docking analysis with Autodock 4.2. Three-dimensional grid was constructed using Autogrid. Docked complexes were visualized using Pymol Viewer. Results: Significant differences in the binding energy and conformations of Dabigatran in the active site of the target was observed between the Ser75Asn, Ala158Val, Asp203Glu, Ala269Ser and Thr290Met variants. The catalytic triad was completely or partially disrupted in the variants suggestive of altered enzyme activity. Conclusion: The binding energy of Dabigatran with the mutant (79Ala, 221Ala, 354Ala and 468Ala) was found to be less than that of the wild type. This indicates that the presence of functional non-synonymous polymorphism in the hCES1 significantly alters the binding of Dabigatran. Hence patients who have this SNP (332G>A, 581C>T, 717C>A, 913C>T, 977C>T) would have decreased hCES1 function, which would result in therapeutic failure or sub-therapeutic drug action. |
