In silico development of new acetylcholinesterase inhibitors.

In this work, we made use of fragment-based drug design (FBDD) and de novo design to obtain more powerful acetylcholinesterase (AChE) inhibitors. AChE is associated with Alzheimer's disease (AD). It was found that the cholinergic pathways in the cerebral cortex are compromised in AD and the accompanying cholinergic deficiency contributes to the cognitive deterioration of AD patients. In the FBDD approach, fragments are docked into the active site of the protein. As fragments are molecular groups with a low number of atoms, it is possible to study their interaction with localized amino acids. Once the interactions are measured, the fragments are organized by affinity and then linked together to form new molecules with a high degree of interaction with the active site. In the other approach, we used the de novo design technique starting from reference drugs used in the AD treatment. These drugs were broken into fragments (seeds). In the growing strategy, fragments were added to each seed, growing new molecules. In the linking strategy, two or more separated seeds were linked with different fragments. Both strategies combined produced a library of more than 2 million compounds. This library was filtered using absorption, distribution, metabolism, and excretion properties. The resulting library with around six thousand compounds was filtered again. In this case, structures with Tanimoto coefficients >.85 were discarded. The final library with 1500 compounds was submitted to docking studies. As a result, 10 compounds with better interaction energy than the reference drugs were obtained.

Diagnostic and therapeutic problems of non perianal fistulas and abscesses in Crohn's disease.

Problems related to the appearance of non perianal fistulas and abscesses are examined in a series of 204 patients operated on for Crohn's disease. Incidence of these complications was 34.3% (70 cases); one or more fistulas were present in 54 patients, associated with abscesses in 13, while abscesses alone were present in 3. The highest incidence was observed in the male sex, in patients over 50 years, and in the presence of stenosing Crohn's lesions (P less than 0.001). On the contrary, the primary site of Crohn's disease does not seem to affect significantly their appearance. The clinical suspect of fistulas or abscesses should be supported with radiographic, endoscopic, echographic and scintiscan findings, even though about 7.2% of fistulas are diagnosed only intraoperatively. Surgical treatment is the most suitable therapeutic management; however enteroenteric and mesenteric fistulas are only relative indications for surgery. TPN is suitable for postoperative enteric fistulas (5 cases). Postoperative morbidity is not different in patients with or without such complications at surgery. Long-term prognosis of non perianal fistulas and abscesses is related only to recurrences of Crohn's disease and their anatomopathologic evolution.