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 Variola virus (VarTMPK) 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 VarTMPK. Our study showed that, despite the structural simplifications, the compounds presented effective energy values in interactions with VarTMPK and HssTMPK and that the guanine could be replaced by a simpler imidazole ring linked to a -NH2 group, without compromising the affinity for VarTMPK. It was also observed that a positive charge in the imidazole ring is important for the selectivity toward VarTMPK 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.

Department of Chemistry Federal University of Viçosa Viçosa MG Brazil

Laboratory of Computational Chemistry Department of Chemistry UFLA Lavras MG Brazil Faculty of Informatics and Management Center for Basic and Applied Research University of Hradec Králové Hradec Králove Czech Republic

Laboratory of Molecular Modeling Applied to Chemical and Biological Defense Military Institute of Engineering Rio de Janeiro RJ Brazil

Laboratory of Molecular Modeling Applied to Chemical and Biological Defense Military Institute of Engineering Rio de Janeiro RJ Brazil Faculty of Informatics and Management Center for Basic and Applied Research University of Hradec Králové Hradec Králove Czech Republic

Laboratory of Organic Synthesis Military Institute of Engineering Rio de Janeiro RJ Brazil

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