An MCASE approach to the search of a cure for Parkinson's Disease.
BACKGROUND
Parkinson's disease is caused by a dopamine deficiency state in the fore brain area. Dopamine receptor agonists, MAO-B inhibitors, and N-Methyl-D-Aspartate (NMDA) receptor antagonists are known to have antiparkinson effect. Levodopa, a dopamine structural analog, is the best currently available medication for the treatment of Parkinsons disease. Unfortunately, it also induces side effects upon long administration time. Thus, multidrug therapy is often used, in which various adjuvants alleviate side effects of levodopa and enhance its antiparkinsonian action.


RESULTS
Computer models have been created for three known antiparkinson mechanisms using the MCASE methodology. New drugs for Parkinsons disease can be designed on the basis of these models. We also speculate that the presence of biophores belonging to different groups can be beneficial and designed some potential drugs along this line. The proposed compounds bear pharmacophores of MAO-B inhibitors, dopamine agonists and NMDA antagonists, which could synergistically enhance their antiparkinson effect.


CONCLUSIONS
The methodology could readily be expanded to other endpoints where drugs with multiple activity mechanisms would be desirable.
Klopman
Gilles
G
Chemistry Department, Case Western Reserve University, 10700, Euclid Avenue, Cleveland, OH 44106, USA. gxk6@po.cwru.edu
Sedykh
Aleksandr
A
D000978:Antiparkinson Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003198:Computer Simulation; D018491:Dopamine Agonists / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D007980:Levodopa / Q000009:adverse effects / Q000627:therapeutic use*; D008996:Monoamine Oxidase Inhibitors / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D008996:Monoamine Oxidase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D007980:Levodopa