Evaluation and synthesis of AZT prodrugs with optimized chemical stabilities: experimental and theoretical analyses

ROYAL SOC CHEMISTRY

Lugar: Cambridge; Año: 2016 vol. 40 p. 2383 - 2383

he design of prodrugs of nucleoside reverse transcriptase inhibitors (NRTIs) constitutes a promisingstrategy to overcome several suboptimal pharmacotherapeutic properties of these kinds of drugs, amongwhich zidovudine (AZT) is the most studied example. The chemical stability of prodrugs is a critical issue inthe context of their pharmacotherapeutic performance since it constitutes a key event in the reconversionof the bioactive NRTIs. In this study, five prodrugs of AZT and lamivudine (3TC) were studied by means ofDFT and classical molecular dynamics (MD) strategies in order to model the reaction coordinates involvedin their chemical hydrolysis, and extend these conclusions to further structure rationalization of prodrugs.Therefore, the inclusion of explicit water molecules was found to be of great relevance to the mentionedreaction coordinates since it allowed a very good correlation between calculated reaction energy valuesand th