COMPUTATIONAL SCIENCE NEW HORIZONS AND RELEVANCE TO PHARMACEUTICAL DESIGN

Computer methods are used extensively in the design and refinement of drug leads, A short summary is given for several computational methods followed by a description of how some of these methods have been appl ied to design drugs targeted to the renin-angiotensin system and to ch olinergic synapses. These methods include quantitative structure-activ ity relationship (QSAR) methods, comparative molecular field analyses (CoMFA), 30 database searching de novo design of ligands, docking and computational alchemy [free energy perturbation (FEP) and thermodynami c integration (MCTI)]. Most of these methods can be used whether or no t detailed structural information about the binding site is available, although without an x-ray structure, the analyses ave move qualitativ e, All of these methods are used extensively in the commercial design of pharmaceuticals. The main problem with most of these methods is in the scoring (ranking) of interactions or matches. Advances in this are a and others (methods development and increases in capabilities of com puters) will increase the predictive power of these methods and help t o speed the time to market of new pharmaceuticals.