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

Abstract

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.

Keywords: Drug design; Variola virus; docking; molecular dynamics simulations; smallpox; thymidylate kinase.

Figure 1.

Selected structures proposed by Guimarães and coworkers (2015) as inhibitors for VarTMPK.

Figure 2.

Structures of the proposed prototypes.

Figure 3.

Best molecular docking poses for prototype 3 inside (a) VarTMPK and (b) HssTMPK. Interacting residues are shown in different colors, and residues belonging to the active site are labeled in red..

Figure 4.

RMSD for the systems formed between the enzymes (in black) and prototype 2 (in red). Left: VarTMPK/prototype 2; right: HssTMPK/prototype 2.

Figure 5.

RMSD for the systems formed between the enzymes (in black) and prototype 3 (in red). Left: VarTMPK/prototype 3; right: HssTMPK/prototype 3.

Figure 6.

RMSD for the systems formed between the enzymes (in black) and prototype 4 (in red). Left: VarTMPK/prototype 4; right: HssTMPK/prototype 4.

Figure 7.

RMSD for the systems formed between the enzymes (in black) and prototype 9 (in red). Left: VarTMPK/prototype 9; right: HssTMPK/prototype 9.

Figure 8.

Plots of mean H-bonds formed by prototypes 3 (left) and 9 (right) inside VarTMPK during the 100 ns of MD simulation.

Figure 9.

Main interactions of the complexes of VarTMPK/prototype 3 (left) and HssTMPK/prototype 3 (right) calculated by MM-PBSA.

Figure 10.

Main interactions of the complexes of VarTMPK/prototype 9 (left) and HssTMPK/prototype 9 (right) calculated by MM-PBSA.