In the present work, we propose to design drugs that target the enzyme dihydrofolate redutase (DHFR) as a means of a novel drug therapy against plague. Potential inhibitors of DHFR from Yersinia pestis (YpDHFR) were selected by virtual screening and subjected to docking, molecular dynamics (MD) simulations, and Poisson-Boltzmann surface area method, in order to evaluate their interactions in the active sites of YpDHFR and human DHFR (HssDHFR). The results suggested selectivity for three compounds that were further used to propose the structures of six new potential selective inhibitors for YpDHFR.

c Department of Chemistry and Biochemistry Concordia University Montreal QC Canada

e Laboratory of Molecular Modeling Chemistry Department Federal University of Lavras Lavras MG Brazil f Faculty of Informatics and Management Center for Basic and Applied Research University of Hradec Kralove Hradec Kralove Czech Republic

Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense Military Institute of Engineering Rio de Janeiro RJ 22290 270 Brazil

Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense Military Institute of Engineering Rio de Janeiro RJ 22290 270 Brazil b Department of Chemistry Federal University of Viçosa Viçosa MG 36570 000 Brazil

Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense Military Institute of Engineering Rio de Janeiro RJ 22290 270 Brazil c Department of Chemistry and Biochemistry Concordia University Montreal QC Canada f Faculty of Informatics and Management Center for Basic and Applied Research University of Hradec Kralove Hradec Kralove Czech Republic

Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense Military Institute of Engineering Rio de Janeiro RJ 22290 270 Brazil d Faculty of Technology University of the State of Rio de Janeiro Resende RJ 27 537 000 Brazil

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