Comprehensive structural and functional characterization of Mycobacterium tuberculosis UDP-NAG enolpyruvyl transferase (Mtb-MurA) and prediction of its accurate binding affinities with inhibitors.

Tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death in the world. One third of the world's population is infected with Mycobacterium tuberculosis (Mtb), the etiologic agent of TB. The bacterial enzyme MurA catalyzes the transfer of enolpyruvate from phosphoenolpyruvate (PEP) to uridine diphospho-N-acetylglucosamine (UNAG), which is the first committed step of bacterial cell wall biosynthesis. In this work, 3D structure model of Mtb-MurA enzyme has been developed for the first time by homology modeling and molecular dynamics simulation techniques. Multiple sequence alignment and 3D structure model provided the putative substrate binding pocket of Mtb-MurA with respect to E. coli MurA. This analysis was helpful in identifying the binding sites and molecular function of the MurA homologue. Molecular docking study was performed on this 3D structure model, using different classes of inhibitors like fosfomycin, cyclic disulfide analog RWJ-3981, pyrazolopyrimidine analog RWJ-110192, purine analog RWJ-140998, 5-sulfonoxy-anthranilic acid derivatives T6361, T6362 and the results showed that the 5-sulfonoxyanthranilic acid derivatives showed the best interaction compared to other inhibitors. We also designed new efficient analogs of T6361 and T6362 which showed even better interaction with Mtb-MurA than the parental 5-sulfonoxy-anthranilic acid derivatives. Further the comparative molecular electrostatic potential and cavity depth analysis of Mtb-MurA suggested several important differences in its substrate and inhibitor binding pocket. Such differences could be exploited in the future for designing a more specific inhibitor for Mtb-MurA enzyme.

Total elbow arthroplasty as primary treatment for distal humeral fractures in elderly patients.

Distal humeral fractures are difficult to treat. In the elderly population, the problems are compounded by osteoporosis and gross comminution. Open reduction and internal fixation for such fractures is sometimes difficult and may be associated with poor results. Total elbow arthroplasty has been suggested as a last-ditch effort to salvage functional use for such difficult fractures in the elderly. We followed seven patients (seven elbows) with a mean age of 81.7 years at the time of injury. Open reduction and internal fixation was considered a difficult option for these fractures. They were treated with a total elbow arthroplasty using the semi-constrained Coonrad-Morrey elbow replacement prosthesis. The duration of follow up at present is between 2 and 4 years. At the latest follow up the mean arc of flexion is 20-130 degrees. Six patients have no pain while one complains of mild pain. All elbows are stable. The Mayo elbow performance score for five elbows is excellent and two scored good. All but one patient are satisfied with the result. One patient developed superficial wound infection which resolved after antibiotic therapy. One patient has developed post-operative triceps weakness. There have been no cases of deep infection, ulnar nerve neuritis or component failure. The rarity of this procedure suggests its very narrow spectrum of indication. We feel that the short-term results do suggest an important role for semi-constrained total elbow arthroplasty in managing carefully selected comminuted distal humeral fractures in the elderly, especially those that cannot be treated by conventional open reduction and internal fixation.