Continuing the work developed by our research group, in the present manuscript, we performed a theoretical study of 10 new structures derived from the antivirals cidofovir and ribavirin, as inhibitor prototypes for the enzyme thymidylate kinase from Variola virus (VarTMPK). The proposed structures were subjected to docking calculations, molecular dynamics simulations, and free energy calculations, using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method, inside the active sites of VarTMPK and human TMPK (HssTMPK). The docking and molecular dynamic studies pointed to structures 2, 3, 4, 6, and 9 as more selective towards VarTMPK. In addition, the free energy data calculated through the MM-PBSA method, corroborated these results. This suggests that these compounds are potential selective inhibitors of VarTMPK and, thus, can be considered as template molecules to be synthesized and experimentally evaluated against smallpox.

Biomedical Research Center University Hospital in Hradec Kralove Sokolska 581 50005 Hradec Kralove Czech Republic

Department of Chemistry Faculty of Science University of Hradec Kralove Rokitanskeho 62 50003 Hradec Kralove Czech Republic

Department of Chemistry Federal University of Viçosa Avenida P H Rolfs s n Centro Viçosa 36570 000 MG Brazil

Department of Chemistry Pontifical Catholic University of Rio de Janeiro Rio de Janeiro 22541 041 Brazil

Department of Neurology of the Medical Faculty of Charles University and University Hospital in Hradec Kralove Sokolska 581 50005 Hradec Kralove Czech Republic

Laboratory of Computational Chemistry Department of Chemistry UFLA Lavras 37200 000 MG Brazil

Laboratory of Molecular Modeling Applied to Chemical and Biological Defense Military Institute of Engineering Praça General Tiburcio 80 Urca Rio de Janeiro 22290 270 Brazil

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