Design of inhibitors of thymidylate kinase from as new selective drugs against smallpox: part II.

Acknowledging the importance of studies toward the development of measures against terrorism and bioterrorism, this study aims to contribute to the design of new prototypes of potential drugs against smallpox. Based on a former study, nine synthetic feasible prototypes of selective inhibitors for thymidylate kinase from (TMPK) were designed and submitted to molecular docking, molecular dynamics simulations and binding energy calculations. The compounds are simplifications of two more complex scaffolds, with a guanine connected to an amide or alcohol through a spacer containing ether and/or amide groups, formerly suggested as promising for the design of selective inhibitors of TMPK. Our study showed that, despite the structural simplifications, the compounds presented effective energy values in interactions with TMPK and TMPK and that the guanine could be replaced by a simpler imidazole ring linked to a -NH group, without compromising the affinity for TMPK. It was also observed that a positive charge in the imidazole ring is important for the selectivity toward TMPK and that an amide group in the spacer does not contribute to selectivity. Finally, prototype 3 was pointed as the most promising to be synthesized and experimentally evaluated. Communicated by Ramaswamy H. Sarma.