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

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.

The oil-contaminated soil diazotroph Azoarcus olearius DQS-4T is genetically and phenotypically similar to the model grass endophyte Azoarcus sp. BH72.

The genome of Azoarcus olearius DQS-4T , a N2 -fixing Betaproteobacterium isolated from oil-contaminated soil in Taiwan, was sequenced and compared with other Azoarcus strains. The genome sequence showed high synteny with Azoarcus sp. BH72, a model endophytic diazotroph, but low synteny with five non-plant-associated strains (Azoarcus CIB, Azoarcus EBN1, Azoarcus KH32C, A. toluclasticus MF63T and Azoarcus PA01). Average Nucleotide Identity (ANI) revealed that DQS-4T shares 98.98% identity with Azoarcus BH72, which should now be included in the species A. olearius. The genome of DQS-4T contained several genes related to plant colonization and plant growth promotion, such as nitrogen fixation, plant adhesion and root surface colonization. In accordance with the presence of these genes, DQS-4T colonized rice (Oryza sativa) and Setaria viridis, where it was observed within the intercellular spaces and aerenchyma mainly of the roots. Although they promote the growth of grasses, the mechanism(s) of plant growth promotion by A. olearius strains is unknown, as the genomes of DQS-4T and BH72 do not contain genes for indole acetic acid (IAA) synthesis nor phosphate solubilization. In spite of its original source, both the genome and behaviour of DQS-4T suggest that it has the capacity to be an endophytic, nitrogen-fixing plant growth-promoting bacterium.