Design of inhibitors of thymidylate kinase from Variola virus as new selective drugs against smallpox

Recently we constructed a homology model of the enzyme thymidylate kinase from Variola virus (VarTMPK) and proposed it as a new target to the drug design against smallpox. In the present work, we used the antivirals cidofovir and acyclovir as reference compounds to choose eleven compounds as leads to the drug design of inhibitors for VarTMPK. Docking and molecular dynamics (MD) studies of the interactions of these compounds inside VarTMPK and human TMPK (HssTMPK) suggest that they compete for the binding region of the substrate and were used to propose the structures of ten new inhibitors for VarTMPK. Further docking and MD simulations of these compounds, inside VarTMPK and HssTMPK, suggest that nine among ten are potential selective inhibitors of VarTMPK. [Display omitted] •Thymidylate kinase from Variola virus (VarTMPK) is proposed as a new drug target.•Cidofovir and acyclovir were used as leads to the drug design of inhibitors.•Ten new inhibitors of VarTMPK were designed based on molecular modeling studies.•Results suggest that nine compounds are potential selective inhibitors of VarTMPK.