Design and discovery of prodrugs of Zidovudine with high affinity to human serum albumin

SCHENFELD, E.M.; QUEVEDO, M.A.

Buenos Aires

Congreso; Congreso de la Sociedad Iberoamericana de Bioinformática (ISCB); 2016

The binding of drugs to plasma transport proteins constitutes a key feature in the therapeutic efficiency of the corresponding compounds. As such, this event requiere a detailed modeling early in the drug discovery and design process. Computational chemistry tools constitutes a very valuable resource to aid in this issue. In the present work, a full workflow aimed to the in silico design of new prodrugs of the anti HIV drug zidovudine with high affinity for human serum albumin (HSA), the main plasma transporter protein, is presented. This workflow included chemical libraries enumeration, molecular docking (MDock) and molecular dynamics (MDyn) studies, as well as free energy (FE) of binding interaction analyses.A reference model of in the interaction betweem HSA and warfarin (WAR), a model compound exhibiting a high affinity for HSA, was constructed based on available crystallographic data. The corresponding interactions fingerprints patterns were constructed by applying MD and FE studies, which was used as a model filter in the screening phase. In a second stage, combinatorial libraries of AZT prodrugs containing aminoacids as carrier moieties were prepared by library enumeration. MDock and and MDyn were perform to predict the corresponding intermolecular interactions complexes with ASH, after which the corresponding interaction fingerprints were calculated. It was observed that 6 AZT prodrugs exhibited homologous fingerprints to those observed for WAR, and this a high predicted affinity for HSA.In conclusión the presented in silico cheminformatic workflow aided in the design of new AZT produgs with high binding to ASH.