COMPUTER AIDED DRUG DESIGN
Although no single drug has been designed solely by computer techniques, the contribution of these methods to drug discovery is no longer a matter of dispute. All the world’s major pharmaceutical and biotechnology companies use computational design tools. At their lowest level the contributions represent the replacement of crude mechanical models by displays of structure which are a much more accurate reflection of molecular reality, capable of demonstrating motion and solvent effects. Beyond this, theoretical calculations permit the computation of binding free energies and other relevant molecular properties. The theoretical tools include empirical molecular mechanics, quantum mechanics and, more recently, statistical mechanics. This latest advance has permitted explicit solvent effects to be incorporated. Underpinning all this work is the availability of high quality computer graphics, largely supported on workstations.
Two distinct categories of research are clearly distinguishable:
crystallography, nmr or homology modelling.
A detailed molecular structure of the target macromolecule, the drug receptor, is known from x-ray
variable activity of otherwise similar molecules.
The target receptor binding site has properties which can only be inferred from a knowledge of the both these types of approach will now be considered and illustrated with some recent examples.