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 applied to design drugs targeted to the renin-angiotensin system and to cholinergic synapses. These methods include quantitative structure-activity relationship (QSAR) methods, comparative molecular field analyses (CoMFA), 3D database searching, de novo design of ligands, docking, and computational alchemy [free energy perturbation (FEP) and thermodynamic integration (MCTI)]. Most of these methods can be used whether or not detailed structural information about the binding site is available, although without an x-ray structure, the analyses are more qualitative. 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 area and others (methods development and increases in capabilities of computers) will increase the predictive power of these methods and help to speed the time to market of new pharmaceuticals. (Trends Cardiovasc Med 1996;6:198-203).