SUPERCOMPUTING-BASED DIMERIC ANALOG APPROACH FOR DRUG OPTIMIZATION

To explore novel and rational ways of developing drugs, we have been u sing supercomputing-based docking as a way of uncovering properties an d events in ligand-receptor complexation that are otherwise impossible to observe. After devising a ''lifelike'' docking program that could be applied to proteins with known 3D structure, we discovered that the Alzheimer drug THA bound not just to acetylcholinesterase's catalytic center but also to a peripheral site. This site was elusive to experi mentalists but is believed to facilitate substrate binding. Accordingl y, we followed a supercomputing-based dimeric analog approach for drug optimization, which culminated in a superior acetylcholinesterase inh ibitor. We describe herein the essence of our approach and its implica tions regarding the utilization of supercomputing in biomedical resear ch. (C) 1998 Elsevier Science B.V. All rights reserved.