ALZHEIMER'S DISEASE DRUG DISCOVERY: NEW ANALYTICAL APPROACHES FOR LEAD SELECTION AND OPTIMIZATION PBA 2009 (20h International Symposium on Pharmaceutical and Biomedical Analysis), Agra, India 01-04 Marzo 2009

The research efforts in drug discovery field are based on the knowledge of the molecular aspects of the disease and on the development of new techniques necessary to investigate the biological systems at molecular level. The selection of new leads is therefore a challenging task and involve various essential steps, the first being the identification/validation of new targets, then the selection of molecules able to bind to the target(s), and finally the study of the effects of hitting the target at molecular, cellular and whole animal level. In the case of Alzheimer’s disease (AD), the most common form of dementia in adults, acetylcholinesterase (AChE) has been the first target for the development of new drugs since the discovery of the cholinergic deficit in the central nervous system. However, basic research showed that cognitive deficit could be due not only to a cholinergic deficit but also to a cascade of biochemical events leading to the accumulation in the brain of proteins such as ß-amyloid and phosphorylated tau. Important targets recently emerged are amyloid fibrillogenesis and BACE1, one of the enzymes which cleave APP (amyloid precursor protein). On the other hand, other non cholinergic role of AChE in the AD has been discovered: some evidences suggest that AChE peripheral binding site may play a key role in the development of senile plaques, accelerating -amyloid peptide (A) deposition. Once the disease targets have been selected, the determination of the activity of the new compounds must be carried out quickly and in a way that allows the verification of the design hypothesis. To this aim, in a first instance, high throughput screening methods (HTS) of a large number of compounds for the selection of few lead compounds are examined, based on immobilized enzyme reactor HPLC systems. Secondly, specific methods, which elucidate the selected compound mechanism of action, are described (surface plasmon resonance, circular dichroism), before the ultimate and most advanced tools, transgenic animal models of the disease, can be used to study the effects of single compounds on the disease phenotype.